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Yao Z, Zhang H, Huang K, Huang G, Xi P, Jiang L, Qin D, Chen F, Li S, Wei R. Niraparib perturbs autophagosome-lysosome fusion in pancreatic ductal adenocarcinoma and exhibits anticancer potential against gemcitabine-resistant PDAC. Transl Oncol 2025; 51:102206. [PMID: 39603206 PMCID: PMC11635771 DOI: 10.1016/j.tranon.2024.102206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/30/2024] [Accepted: 11/17/2024] [Indexed: 11/29/2024] Open
Abstract
While poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have achieved specific clinical benefits in a subset of pancreatic ductal adenocarcinoma (PDAC) patients, the potential role of the PARPi niraparib in PDAC necessitates further exploration. In this study, we demonstrated that Niraparib exhibited a pronounced inhibitory effect on autophagy in PDAC both in vitro and in vivo. Mechanistically, this inhibition was primarily attributed to niraparib's ability to disrupt the fusion process between autophagosomes and lysosomes, while potentially exerting a relatively minor impact on the initial stage of autophagy. The blockade effect observed may be mediated via modulation of the ERK signaling pathway, and this effect can be mitigated by the application of an ERK inhibitor (FR180204). Notably, the combined treatment regimen of niraparib and gemcitabine failed to elicit the anticipated synergistic effects in wild-type PANC-1 cells, instead exhibiting pronounced antagonistic interactions. However, in gemcitabine-resistant PANC-1 cells, the combination of niraparib and gemcitabine exhibited modest additive effects. Furthermore, niraparib demonstrated a heightened cytotoxic potency against gemcitabine-resistant PANC-1 cells compared to wild-type PANC-1 cells, both in vitro and in vivo. Our research established that niraparib inhibits late-stage autophagy in PDAC, potentially representing a valuable salvage therapy for gemcitabine-resistant PDAC. Further clinical studies are justified.
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Affiliation(s)
- Zehui Yao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Huihui Zhang
- Center for Orthopaedic Surgery, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, 510060, China
| | - Kewei Huang
- Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Guizhong Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Pu Xi
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Lingmin Jiang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Dailei Qin
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Fan Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - Shengping Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - Ran Wei
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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Kalli M, Mpekris F, Charalambous A, Michael C, Stylianou C, Voutouri C, Hadjigeorgiou AG, Papoui A, Martin JD, Stylianopoulos T. Mechanical forces inducing oxaliplatin resistance in pancreatic cancer can be targeted by autophagy inhibition. Commun Biol 2024; 7:1581. [PMID: 39604540 PMCID: PMC11603328 DOI: 10.1038/s42003-024-07268-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024] Open
Abstract
Pancreatic cancer remains one of the most lethal malignancies, with limited treatment options and poor prognosis. A common characteristic among pancreatic cancer patients is the biomechanically altered tumor microenvironment (TME), which among others is responsible for the elevated mechanical stresses in the tumor interior. Although significant research has elucidated the effect of mechanical stress on cancer cell proliferation and migration, it has not yet been investigated how it could affect cancer cell drug sensitivity. Here, we demonstrated that mechanical stress triggers autophagy activation, correlated with increased resistance to oxaliplatin treatment in pancreatic cancer cells. Our results demonstrate that inhibition of autophagy using hydroxychloroquine (HCQ) enhanced the oxaliplatin-induced apoptotic cell death in pancreatic cancer cells exposed to mechanical stress. The combined treatment of HCQ with losartan, a known modulator of mechanical abnormalities in tumors, synergistically enhanced the therapeutic efficacy of oxaliplatin in murine pancreatic tumor models. Furthermore, our study revealed that the use of HCQ enhanced the efficacy of losartan to alleviate mechanical stress levels and restore blood vessel integrity beyond its role in autophagy modulation. These findings underscore the potential of co-targeting mechanical stresses and autophagy as a promising therapeutic strategy to overcome drug resistance and increase chemotherapy efficacy.
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Affiliation(s)
- Maria Kalli
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
| | - Fotios Mpekris
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Antonia Charalambous
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Christina Michael
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Chrystalla Stylianou
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Chrysovalantis Voutouri
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Andreas G Hadjigeorgiou
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Antonia Papoui
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | | | - Triantafyllos Stylianopoulos
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
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3
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Ni R, Hu Z, Tao R. Advances of immune-checkpoint inhibition of CTLA-4 in pancreatic cancer. Biomed Pharmacother 2024; 179:117430. [PMID: 39260322 DOI: 10.1016/j.biopha.2024.117430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 09/05/2024] [Accepted: 09/05/2024] [Indexed: 09/13/2024] Open
Abstract
Targeting checkpoints for immune cell activation has been acknowledged known as one of the most effective way to activate anti-tumor immune responses. Among them, drugs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for clinical treatment though several more are in advanced stages of development, which demonstrated durable response rates and manageable safety profile. However, its therapy efficacy is unsatisfactory in pancreatic cancer (PC), which can be limited by the overall condition of patients, the pathological type of PC, the expression level of tumor related genes, etc. To improve clinical efficiency, various researches have been conducted, and the efficacy of combination therapy showed significantly improvement compared to monotherapy. This review analyzed current strategies based on anti-CTLA-4 combination immunotherapy, providing totally new idea for future research.
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Affiliation(s)
- Ran Ni
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China; General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zhiming Hu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China; Department of Hepatobiliary & Pancreatic Surgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China.
| | - Ran Tao
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
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Hwang YK, Lee DH, Lee EC, Oh JS. Importance of Autophagy Regulation in Glioblastoma with Temozolomide Resistance. Cells 2024; 13:1332. [PMID: 39195222 PMCID: PMC11353125 DOI: 10.3390/cells13161332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 08/01/2024] [Accepted: 08/08/2024] [Indexed: 08/29/2024] Open
Abstract
Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling of cellular components, has been found to play an important role in GBM pathogenesis and response to therapy. Autophagy plays a dual role in promoting tumor survival and apoptosis, and here we discuss the complex interplay between autophagy and GBM. We summarize the mechanisms underlying autophagy dysregulation in GBM, including PI3K/AKT/mTOR signaling, which is most active in brain tumors, and EGFR and mutant EGFRvIII. We also review potential therapeutic strategies that target autophagy for the treatment of GBM, such as autophagy inhibitors used in combination with the standard of care, TMZ. We discuss our current understanding of how autophagy is involved in TMZ resistance and its role in glioblastoma development and survival.
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Affiliation(s)
- Young Keun Hwang
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.K.H.); (E.C.L.)
| | - Dong-Hun Lee
- Industry-Academic Cooperation Foundation, The Catholic University of Korea, 222, Banpo-daro, Seocho-gu, Seoul 06591, Republic of Korea;
| | - Eun Chae Lee
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.K.H.); (E.C.L.)
| | - Jae Sang Oh
- Department of Neurosurgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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Phadte P, Bishnu A, Dey P, M M, Mehrotra M, Singh P, Chakrabarty S, Majumdar R, Rekhi B, Patra M, De A, Ray P. Autophagy-mediated ID1 turnover dictates chemo-resistant fate in ovarian cancer stem cells. J Exp Clin Cancer Res 2024; 43:222. [PMID: 39123206 PMCID: PMC11316295 DOI: 10.1186/s13046-024-03147-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND The mechanisms enabling dynamic shifts between drug-resistant and drug-sensitive states in cancer cells are still underexplored. This study investigated the role of targeted autophagic protein degradation in regulating ovarian cancer stem cell (CSC) fate decisions and chemo-resistance. METHODS Autophagy levels were compared between CSC-enriched side population (SP) and non-SP cells (NSP) in multiple ovarian cancer cell lines using immunoblotting, immunofluorescence, and transmission electron microscopy. The impact of autophagy modulation on CSC markers and differentiation was assessed by flow cytometry, immunoblotting and qRT-PCR. In silico modeling and co-immunoprecipitation identified ID1 interacting proteins. Pharmacological and genetic approaches along with Annexin-PI assay, ChIP assay, western blotting, qRT-PCR and ICP-MS were used to evaluate effects on cisplatin sensitivity, apoptosis, SLC31A1 expression, promoter binding, and intracellular platinum accumulation in ID1 depleted backdrop. Patient-derived tumor spheroids were analyzed for autophagy and SLC31A1 levels. RESULTS Ovarian CSCs exhibited increased basal autophagy compared to non-CSCs. Further autophagy stimulation by serum-starvation and chemical modes triggered proteolysis of the stemness regulator ID1, driving the differentiation of chemo-resistant CSCs into chemo-sensitive non-CSCs. In silico modeling predicted TCF12 as a potent ID1 interactor, which was validated by co-immunoprecipitation. ID1 depletion freed TCF12 to transactivate the cisplatin influx transporter SLC31A1, increasing intracellular cisplatin levels and cytotoxicity. Patient-derived tumor spheroids exhibited a functional association between autophagy, ID1, SLC31A1, and platinum sensitivity. CONCLUSIONS This study reveals a novel autophagy-ID1-TCF12-SLC31A1 axis where targeted autophagic degradation of ID1 enables rapid remodeling of CSCs to reverse chemo-resistance. Modulating this pathway could counter drug resistance in ovarian cancer.
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Affiliation(s)
- Pratham Phadte
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Aniketh Bishnu
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Pranay Dey
- Molecular Functional Imaging Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Manikandan M
- Laboratory of Medicinal Chemistry and Cell Biology, Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, 400005, India
| | - Megha Mehrotra
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Prerna Singh
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Shritama Chakrabarty
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
- Indian Institute of Science Education and Research, Bhopal, 462066, India
| | - Rounak Majumdar
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
- Indian Institute of Science Education and Research, Kolkata, 741246, India
| | - Bharat Rekhi
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
- Department of Pathology, Tata Memorial Hospital, Mumbai, 400012, India
| | - Malay Patra
- Laboratory of Medicinal Chemistry and Cell Biology, Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, 400005, India
| | - Abhijit De
- Molecular Functional Imaging Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Pritha Ray
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India.
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India.
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Kovale L, Singh MK, Kim J, Ha J. Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer. Int J Mol Sci 2024; 25:8647. [PMID: 39201332 PMCID: PMC11354724 DOI: 10.3390/ijms25168647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/30/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
Cancer stem cells represent a resilient subset within the tumor microenvironment capable of differentiation, regeneration, and resistance to chemotherapeutic agents, often using dormancy as a shield. Their unique properties, including drug resistance and metastatic potential, pose challenges for effective targeting. These cells exploit certain metabolic processes for their maintenance and survival. One of these processes is autophagy, which generally helps in energy homeostasis but when hijacked by CSCs can help maintain their stemness. Thus, it is often referred as an Achilles heel in CSCs, as certain cancers tend to depend on autophagy for survival. Autophagy, while crucial for maintaining stemness in cancer stem cells (CSCs), can also serve as a vulnerability in certain contexts, making it a complex target for therapy. Regulators of autophagy like AMPK (5' adenosine monophosphate-activated protein kinase) also play a crucial role in maintaining CSCs stemness by helping CSCs in metabolic reprogramming in harsh environments. The purpose of this review is to elucidate the interplay between autophagy and AMPK in CSCs, highlighting the challenges in targeting autophagy and discussing therapeutic strategies to overcome these limitations. This review focuses on previous research on autophagy and its regulators in cancer biology, particularly in CSCs, addresses the remaining unanswered questions, and potential targets for therapy are also brought to attention.
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Affiliation(s)
- Lochana Kovale
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
| | - Manish Kumar Singh
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
| | - Joungmok Kim
- Department of Oral Biochemistry and Molecular Biology, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Joohun Ha
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
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Cheng CW, Liu YF, Liao WL, Chen PM, Hung YT, Lee HJ, Cheng YC, Wu PE, Lu YS, Shen CY. miR-622 Increases miR-30a Expression through Inhibition of Hypoxia-Inducible Factor 1α to Improve Metastasis and Chemoresistance in Human Invasive Breast Cancer Cells. Cancers (Basel) 2024; 16:657. [PMID: 38339408 PMCID: PMC10854867 DOI: 10.3390/cancers16030657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 01/29/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024] Open
Abstract
Hypoxia-inducible factor 1α (HIF-1α) plays a pivotal role in the survival, metastasis, and response to treatment of solid tumors. Autophagy serves as a mechanism for tumor cells to eliminate misfolded proteins and damaged organelles, thus promoting invasiveness, metastasis, and resistance to treatment under hypoxic conditions. MicroRNA (miRNA) research underscores the significance of these non-coding molecules in regulating cancer-related protein synthesis across diverse contexts. However, there is limited reporting on miRNA-mediated gene expression studies, especially with respect to epithelial-mesenchymal transition (EMT) and autophagy in the context of hypoxic breast cancer. Our study reveals decreased levels of miRNA-622 (miR-622) and miRNA-30a (miR-30a) in invasive breast cancer cells compared to their non-invasive counterparts. Inducing miR-622 suppresses HIF-1α protein expression, subsequently activating miR-30a transcription. This cascade results in reduced invasiveness and migration of breast cancer cells by inhibiting EMT markers, such as Snail, Slug, and vimentin. Furthermore, miR-30a negatively regulates beclin 1, ATG5, and LC3-II and inhibits Akt protein phosphorylation. Consequently, this improves the sensitivity of invasive MDA-MB-231 cells to docetaxel treatment. In conclusion, our study highlights the therapeutic potential of inducing miR-622 to promote miR-30a expression and thus disrupt HIF-1α-associated EMT and autophagy pathways. This innovative strategy presents a promising approach to the treatment of aggressive breast cancer.
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Affiliation(s)
- Chun-Wen Cheng
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (P.-M.C.); (Y.-T.H.)
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Yu-Fan Liu
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung 40201, Taiwan;
| | - Wen-Ling Liao
- School of Medicine, China Medical University, Taichung 40604, Taiwan;
- Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung 40604, Taiwan
| | - Po-Ming Chen
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (P.-M.C.); (Y.-T.H.)
| | - Yueh-Tzu Hung
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (P.-M.C.); (Y.-T.H.)
| | - Huei-Jane Lee
- Department of Biochemistry, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan;
| | - Yu-Chun Cheng
- Department of Internal Medicine, Cathay General Hospital, Taipei 10629, Taiwan;
| | - Pei-Ei Wu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan;
| | - Yen-Shen Lu
- Department of Oncology, National Taiwan University Hospital, Taipei 10022, Taiwan;
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10022, Taiwan
| | - Chen-Yang Shen
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan;
- College of Public Health, China Medical University, Taichung 40604, Taiwan
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Short peptide domains of the Wnt inhibitor sFRP4 target ovarian cancer stem cells by neutralizing the Wnt β-catenin pathway, disrupting the interaction between β-catenin and CD24 and suppressing autophagy. Life Sci 2023; 316:121384. [PMID: 36646377 DOI: 10.1016/j.lfs.2023.121384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/02/2023] [Accepted: 01/07/2023] [Indexed: 01/15/2023]
Abstract
AIMS One of the hallmarks of cancer stem cells (CSC) is hyperactive Wnt β-catenin signaling due to the decreased presence of Wnt antagonists such as secreted frizzled related protein 4 (SFRP4). Cysteine-rich domain (CRD) and netrin-like domain (NLD) are the two functional domains of SFRP4 having anti-tumor properties. In this study, we have explored the effectiveness of short micropeptides SC-301 (from CRD) and SC-401 (from NLD) on CSC properties, EMT, apoptosis and autophagy in ovarian CSCs enriched from PA-1 and SKOV-3 cell lines. MAIN METHODS Gene expression analysis, Western blot and immunocytochemistry were performed on ovarian CSCs to evaluate the inhibitory potential of micropeptides to various CSC associated oncogenic properties. Co-immunoprecipitation was performed to detect the binding of CD24 to β-catenin protein complex. CYTO-ID Autophagy Detection Kit 2.0 was used to monitor autophagic flux in peptide treated CSCs. KEY FINDINGS It is clearly seen that the micropeptides derived from both the domains inhibit Wnt pathway, initiate apoptosis, inhibit migration and chemosensitize CSCs. Specifically, CD24, a defining marker of ovarian CSC was suppressed by peptide treatment. Notably, interaction between CD24 and β-catenin was disrupted upon peptide treatment. SFRP4 peptide treatment also suppressed the autophagic process which is crucial for CSC survival. SIGNIFICANCE The study demonstrated that although both peptides have inhibitory effects, SC-401 was emphatically more effective in targeting CSC properties and down regulating the Wnt β-catenin machinery.
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Glucocorticoid-induced microRNA-378 signaling mediates the progression of pancreatic cancer by enhancing autophagy. Cell Death Dis 2022; 13:1052. [PMID: 36535942 PMCID: PMC9763328 DOI: 10.1038/s41419-022-05503-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/06/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022]
Abstract
Glucocorticoids (GCs) are widely used in tumor therapy to reduce tumor growth, inflammation, edema, and other side effects. Controversially, GCs may also cause the progression of highly aggressive pancreatic ductal adenocarcinoma (PDAC). Because microRNA (miR) and autophagy signaling support the invasive growth of PDAC, we asked whether these mechanisms may be targeted by GCs. Six established human PDAC cell lines, tissue from patients who received GC medication (n = 35) prior to surgery, or not (n = 35), and tumor xenografts were examined by RT‒qPCR, transmission electron microscopy (TEM), monodansylcadaverine (MDC) staining, immunohistochemistry, in situ hybridization, gene array and Kaplan‒Meier analysis with bioinformatics, and MTT, western blot, colony, spheroid, migration, and invasion assays. We found that various GCs, including dexamethasone (DEX), induced typical features of macroautophagy with the appearance of autolysosomes, enhanced LC3-II, decreased SQSTM1/p62 expression and induced epithelial-mesenchymal transition (EMT) and gemcitabine resistance. The GC receptor (GR) antagonist mifepristone (RU486) counteracted DEX-induced autophagy features, suggesting that the GC-GR complex is involved in the induction of autophagy. The autophagy-related miR-378i and miR-378a-3p were selected as the top upregulated candidates, and their high expression in PDAC patient tissue correlated with low survival. siRNA-mediated downregulation of miR-378 inhibited DEX-induced autophagy, and tumor progression. Bioinformatics confirmed the contribution of miR-378 to the regulation of signaling networks involved in GC-induced autophagy and tumor progression. The construction of a molecular docking model revealed stable binding of miR-378 to the DEX-GR complex, suggesting direct regulation. These substantial, novel, in-depth data reveal that GCs favor autophagy-mediated cancer progression by inducing miR-378 and GR binding and implicate GR and miR-378 as new therapeutic targets.
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10
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Andreucci E, Peppicelli S, Ruzzolini J, Bianchini F, Calorini L. Physicochemical aspects of the tumour microenvironment as drivers of vasculogenic mimicry. Cancer Metastasis Rev 2022; 41:935-951. [PMID: 36224457 PMCID: PMC9758104 DOI: 10.1007/s10555-022-10067-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/04/2022] [Indexed: 01/25/2023]
Abstract
Tumour vascularisation is vital for cancer sustainment representing not only the main source of nutrients and oxygen supply but also an escape route for single or clustered cancer cells that, once detached from the primary mass, enter the blood circulation and disseminate to distant organs. Among the mechanisms identified to contribute to tumour vascularisation, vasculogenic mimicry (VM) is gaining increasing interest in the scientific community representing an intriguing target for cancer treatment. VM indeed associates with highly aggressive tumour phenotypes and strongly impairs patient outcomes. Differently from vessels of healthy tissues, tumour vasculature is extremely heterogeneous and tortuous, impeding efficient chemotherapy delivery, and at the meantime hyperpermeable and thus extremely accessible to metastasising cancer cells. Moreover, tumour vessel disorganisation creates a self-reinforcing vicious circle fuelling cancer malignancy and progression. Because of the inefficient oxygen delivery and metabolic waste removal from tumour vessels, many cells within the tumour mass indeed experience hypoxia and acidosis, now considered hallmarks of cancer. Being strong inducers of vascularisation, therapy resistance, inflammation and metastasis, hypoxia and acidosis create a permissive microenvironment for cancer progression and dissemination. Along with these considerations, we decided to focus our attention on the relationship between hypoxia/acidosis and VM. Indeed, besides tumour angiogenesis, VM is strongly influenced by both hypoxia and acidosis, which could potentiate each other and fuel this vicious circle. Thus, targeting hypoxia and acidosis may represent a potential target to treat VM to impair tumour perfusion and cancer cell sustainment.
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Affiliation(s)
- Elena Andreucci
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Silvia Peppicelli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
| | - Jessica Ruzzolini
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Francesca Bianchini
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Lido Calorini
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
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Troumpoukis D, Papadimitropoulou A, Charalampous C, Kogionou P, Palamaris K, Sarantis P, Serafimidis I. Targeting autophagy in pancreatic cancer: The cancer stem cell perspective. Front Oncol 2022; 12:1049436. [PMID: 36505808 PMCID: PMC9730023 DOI: 10.3389/fonc.2022.1049436] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/09/2022] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer is currently the seventh leading cause of cancer-related deaths worldwide, with the estimated death toll approaching half a million annually. Pancreatic ductal adenocarcinoma (PDAC) is the most common (>90% of cases) and most aggressive form of pancreatic cancer, with extremely poor prognosis and very low survival rates. PDAC is initiated by genetic alterations, usually in the oncogene KRAS and tumor suppressors CDKN2A, TP53 and SMAD4, which in turn affect a number of downstream signaling pathways that regulate important cellular processes. One of the processes critically altered is autophagy, the mechanism by which cells clear away and recycle impaired or dysfunctional organelles, protein aggregates and other unwanted components, in order to achieve homeostasis. Autophagy plays conflicting roles in PDAC and has been shown to act both as a positive effector, promoting the survival of pancreatic tumor-initiating cells, and as a negative effector, increasing cytotoxicity in uncontrollably expanding cells. Recent findings have highlighted the importance of cancer stem cells in PDAC initiation, progression and metastasis. Pancreatic cancer stem cells (PaCSCs) comprise a small subpopulation of the pancreatic tumor, characterized by cellular plasticity and the ability to self-renew, and autophagy has been recognised as a key process in PaCSC maintenance and function, simultaneously suggesting new strategies to achieve their selective elimination. In this review we evaluate recent literature that links autophagy with PaCSCs and PDAC, focusing our discussion on the therapeutic implications of pharmacologically targeting autophagy in PaCSCs, as a means to treat PDAC.
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Affiliation(s)
- Dimitrios Troumpoukis
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | | | - Chrysanthi Charalampous
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Paraskevi Kogionou
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Kostas Palamaris
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Serafimidis
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece,*Correspondence: Ioannis Serafimidis,
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12
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Song M, Lu Q, Xu M, Li Y, Zhao Y, Gong C, Ou X. The global research and emerging trends in autophagy of pancreatic cancer: A bibliometric and visualized study. Front Oncol 2022; 12:987026. [PMID: 36263211 PMCID: PMC9574366 DOI: 10.3389/fonc.2022.987026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/15/2022] [Indexed: 11/30/2022] Open
Abstract
Objective To present the global research features and hotspots, and forecast the emerging trends by conducting a bibliometric analysis based on literature related to autophagy of pancreatic cancer from 2011 to 2022. Methods The literature data regarding autophagy of pancreatic cancer were retrieved and downloaded from the Web of Science Core Collection (WOSCC) from Clarivate Analytics on June 10th, 2022. VOSviewer (version 1.6.18) was used to perform the bibliometric analysis. Results A total of 616 studies written by 3993 authors, covered 45 countries and 871 organizations, published in 263 journals and co-cited 28152 references from 2719 journals. China (n=260, 42.2%) and the United States (n=211, 34.3%) were the most frequent publishers and collaborated closely. However, publications from China had a low average number of citations (25.35 times per paper). The output of University of Texas MD Anderson Cancer Center ranked the first with 26 papers (accounting for 4.2% of the total publications). Cancers (n=23, 3.7%; Impact Factor = 6.639) published most papers in this field and was very pleasure to accept related researches. Daolin Tang and Rui Kang published the most papers (n=18, respectively). The research hotspots mainly focused on the mechanisms of autophagy in tumor onset and progression, the role of autophagy in tumor apoptosis, and autophagy-related drugs in treating pancreatic cancer (especially combined therapy). The emerging topics were chemotherapy resistance mediated by autophagy, tumor microenvironment related to autophagy, autophagy-depended epithelial-mesenchymal transition (EMT), mitophagy, and the role of autophagy in tumor invasion. Conclusion Attention has been increasing in autophagy of pancreatic cancer over the past 12 years. Our results undoubtedly provide scholars with new clues and ideas in this field.
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Affiliation(s)
- Mingyang Song
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Qin Lu
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Min Xu
- Department of Human Anatomy, School of Medicine, Southeast University, Nanjing, China
| | - Yajie Li
- Department of Gerontology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yawen Zhao
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Chen Gong
- Department of Gastroenterology, Taicang Affiliated Hospital of Soochow University, The First People’s Hospital of Taicang, Jiangsu, China
- *Correspondence: Xilong Ou, ; Chen Gong,
| | - Xilong Ou
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
- *Correspondence: Xilong Ou, ; Chen Gong,
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13
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Zuzčák M, Trnka J. Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review). Int J Oncol 2022; 61:93. [PMID: 35730611 PMCID: PMC9256076 DOI: 10.3892/ijo.2022.5383] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/10/2022] [Indexed: 11/28/2022] Open
Abstract
Pancreatic cancer (PC) has one of the highest fatality rates and the currently available therapeutic options are not sufficient to improve its overall poor prognosis. In addition to insufficient effectiveness of anticancer treatments, the lack of clear early symptoms and early metastatic spread maintain the PC survival rates at a low level. Metabolic reprogramming is among the hallmarks of cancer and could be exploited for the diagnosis and treatment of PC. PC is characterized by its heterogeneity and, apart from molecular subtypes, the identification of metabolic subtypes in PC could aid in the development of more individualized therapeutic approaches and may lead to improved clinical outcomes. In addition to the deregulated utilization of glucose in aerobic glycolysis, PC cells can use a wide range of substrates, including branched‑chain amino acids, glutamine and lipids to fulfil their energy requirements, as well as biosynthetic needs. The tumor microenvironment in PC supports tumor growth, metastatic spread, treatment resistance and the suppression of the host immune response. Moreover, reciprocal interactions between cancer and stromal cells enhance their metabolic reprogramming. PC stem cells (PCSCs) with an increased resistance and distinct metabolic properties are associated with disease relapses and cancer spread, and represent another significant candidate for therapeutic targeting. The present review discusses the metabolic signatures observed in PC, a disease with a multifaceted and often transient metabolic landscape. In addition, the metabolic pathways utilized by PC cells, as well as stromal cells are discussed, providing examples of how they could present novel targets for therapeutic interventions and elaborating on how interactions between the various cell types affect their metabolism. Furthermore, the importance of PCSCs is discussed, focusing specifically on their metabolic adaptations.
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Affiliation(s)
- Michal Zuzčák
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
- Center for Research on Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
| | - Jan Trnka
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
- Center for Research on Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic
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14
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Kapoor-Narula U, Lenka N. Cancer stem cells and tumor heterogeneity: Deciphering the role in tumor progression and metastasis. Cytokine 2022; 157:155968. [PMID: 35872504 DOI: 10.1016/j.cyto.2022.155968] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 07/08/2022] [Accepted: 07/13/2022] [Indexed: 11/03/2022]
Abstract
Tumor heterogeneity, in principle, reflects the variation among different cancer cell populations. It can be termed inter- or intra-tumoral heterogeneity, respectively, based on its occurrence in various tissues from diverse patients or within a single tumor. The intra-tumoral heterogeneity is one of the leading causes of cancer progression and treatment failure, with the cancer stem cells (CSCs) contributing immensely to the same. These niche cells, similar to normal stem cells, possess the characteristics of self-renewal and differentiation into multiple cell types. Moreover, CSCs contribute to tumor growth and surveillance by promoting recurrence, metastasis, and therapeutic resistance. Diverse factors, including intracellular signalling pathways and tumor microenvironment (TME), play a vital role in regulating these CSCs. Although a panel of markers is considered to identify the CSC pool in various cancers, further research is needed to discriminate cancer-specific CSC markers in those. CSCs have also been found to be promising therapeutic targets for cancer therapy. Several small molecules, natural compounds, antibodies, chimeric antigen receptor T (CAR-T) cells, and CAR-natural killer (CAR-NK) cells have emerged as therapeutic tools for specific targeting of CSCs. Interestingly, many of these are in clinical trials too. Despite being a much-explored avenue of research for years, and we have come to understand its nitty-gritty, there is still a tremendous gap in our knowledge concerning its precise genesis and regulation. Hence, a concrete understanding is needed to assess the CSC-TME link and how to target different cancer-specific CSCs by designing newer tools. In this review, we have summarized CSC, its causative, different pathways and factors regulating its growth, association with tumor heterogeneity, and last but not least, discussed many of the promising CSC-targeted therapies for combating cancer metastasis.
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15
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Gillson J, Abd El-Aziz YS, Leck LYW, Jansson PJ, Pavlakis N, Samra JS, Mittal A, Sahni S. Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target. Cancers (Basel) 2022; 14:3528. [PMID: 35884592 PMCID: PMC9315706 DOI: 10.3390/cancers14143528] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/10/2022] [Accepted: 07/11/2022] [Indexed: 01/18/2023] Open
Abstract
Pancreatic cancer is known to have the lowest survival outcomes among all major cancers, and unfortunately, this has only been marginally improved over last four decades. The innate characteristics of pancreatic cancer include an aggressive and fast-growing nature from powerful driver mutations, a highly defensive tumor microenvironment and the upregulation of advantageous survival pathways such as autophagy. Autophagy involves targeted degradation of proteins and organelles to provide a secondary source of cellular supplies to maintain cell growth. Elevated autophagic activity in pancreatic cancer is recognized as a major survival pathway as it provides a plethora of support for tumors by supplying vital resources, maintaining tumour survival under the stressful microenvironment and promoting other pathways involved in tumour progression and metastasis. The combination of these features is unique to pancreatic cancer and present significant resistance to chemotherapeutic strategies, thus, indicating a need for further investigation into therapies targeting this crucial pathway. This review will outline the autophagy pathway and its regulation, in addition to the genetic landscape and tumor microenvironment that contribute to pancreatic cancer severity. Moreover, this review will also discuss the mechanisms of novel therapeutic strategies that inhibit autophagy and how they could be used to suppress tumor progression.
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Affiliation(s)
- Josef Gillson
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
| | - Yomna S. Abd El-Aziz
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta 31527, Egypt
| | - Lionel Y. W. Leck
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Patric J. Jansson
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Nick Pavlakis
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
| | - Jaswinder S. Samra
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, St Leonards, Sydney, NSW 2065, Australia
- Australian Pancreatic Centre, St Leonards, Sydney, NSW 2065, Australia
| | - Anubhav Mittal
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, St Leonards, Sydney, NSW 2065, Australia
- Australian Pancreatic Centre, St Leonards, Sydney, NSW 2065, Australia
- School of Medicine, University of Notre Dame, Darlinghurst, Sydney, NSW 2010, Australia
| | - Sumit Sahni
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Australian Pancreatic Centre, St Leonards, Sydney, NSW 2065, Australia
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16
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Rezayatmand H, Razmkhah M, Razeghian-Jahromi I. Drug resistance in cancer therapy: the Pandora's Box of cancer stem cells. Stem Cell Res Ther 2022; 13:181. [PMID: 35505363 PMCID: PMC9066908 DOI: 10.1186/s13287-022-02856-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 04/14/2022] [Indexed: 12/18/2022] Open
Abstract
Drug resistance is the main culprit of failure in cancer therapy that may lead to cancer relapse. This resistance mostly originates from rare, but impactful presence of cancer stem cells (CSCs). Ability to self-renewal and differentiation into heterogeneous cancer cells, and harboring morphologically and phenotypically distinct cells are prominent features of CSCs. Also, CSCs substantially contribute to metastatic dissemination. They possess several mechanisms that help them to survive even after exposure to chemotherapy drugs. Although chemotherapy is able to destroy the bulk of tumor cells, CSCs are left almost intact, and make tumor entity resistant to treatment. Eradication of a tumor mass needs complete removal of tumor cells as well as CSCs. Therefore, it is important to elucidate key features underlying drug resistance raised by CSCs in order to apply effective treatment strategies. However, the challenging point that threatens safety and specificity of chemotherapy is the common characteristics between CSCs and normal peers such as signaling pathways and markers. In the present study, we tried to present a comprehensive appraisal on CSCs, mechanisms of their drug resistance, and recent therapeutic methods targeting this type of noxious cells.
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Affiliation(s)
| | - Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Iman Razeghian-Jahromi
- Cardiovascular Research Center, Shiraz University of Medical Sciences, 3rd Floor, Mohammad Rasoolallah Research Tower, Namazi Hospital, Shiraz, Iran.
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17
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Huldani H, Jasim SA, Sergeenva KN, Bokov DO, Abdelbasset WK, Turakulov R, Al-Gazally ME, Ahmadzadeh B, Jawhar ZH, Siahmansouri H. Mechanisms of cancer stem cells drug resistance and the pivotal role of HMGA2. Pathol Res Pract 2022; 234:153906. [PMID: 35468338 DOI: 10.1016/j.prp.2022.153906] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/02/2022] [Accepted: 04/15/2022] [Indexed: 11/24/2022]
Abstract
Nowadays, the focus of researchers is on perceiving the heterogeneity observed in a tumor. The researchers studied the role of a specific subset of cancer cells with high resistance to traditional treatments, recurrence, and unregulated metastasis. This small population of tumor cells that have stem-cell-like specifications was named Cancer Stem Cells (CSCs). The unique features that distinguish this type of cancer cell are self-renewing, generating clones of the tumor, plasticity, recurrence, and resistance to therapies. There are various mechanisms that contribute to the drug resistance of CSCs, such as CSCs markers, Epithelial mesenchymal transition, hypoxia, other cells, inflammation, and signaling pathways. Recent investigations have revealed the primary role of HMGA2 in the development and invasion of cancer cells. Importantly, HMGA2 also plays a key role in resistance to treatment through their function in the drug resistance mechanisms of CSCs and challenge it. Therefore, a deep understanding of this issue can provide a clearer perspective for researchers in the face of this problem.
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Affiliation(s)
- Huldani Huldani
- Department of Physiology, Lambung Mangkurat University, Banjarmasin, South Borneo, Indonesia
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-Maarif University College, Al-Anbar-Ramadi, Iraq
| | - Klunko Nataliya Sergeenva
- Department of post-graduate and doctoral programs, Russian New University, Building 5, Radio Street, Moscow City, Russian Federation
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., Bldg. 2, Moscow 119991, Russian Federation
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia; Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Rustam Turakulov
- Department of Internal diseases, Tashkent Medical Academy, Tashkent, Uzbekistan
| | | | - Behnam Ahmadzadeh
- Doctoral School of the University of Szczecin, Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland
| | - Zanko Hassan Jawhar
- Department of Medical Laboratory Science, College of Health Science, Lebanese French University, Kurdistan Region, Iraq
| | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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18
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A perspective on the role of autophagy in cancer. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166262. [PMID: 34481059 DOI: 10.1016/j.bbadis.2021.166262] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/20/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022]
Abstract
Autophagy refers to a ubiquitous set of catabolic pathways required to achieve proper cellular homeostasis. Aberrant autophagy has been implicated in a multitude of diseases including cancer. In this review, we highlight pioneering and groundbreaking research that centers on delineating the role of autophagy in cancer initiation, proliferation and metastasis. First, we discuss the autophagy-related (ATG) proteins and their respective roles in the de novo formation of autophagosomes and the subsequent delivery of cargo to the lysosome for recycling. Next, we touch upon the history of cancer research that centers upon ATG proteins and regulatory mechanisms that control an appropriate autophagic response and how these are altered in the diseased state. Then, we discuss the various discoveries that led to the idea of autophagy as a double-edged sword when it comes to cancer therapy. This review also briefly narrates how different types of autophagy-selective macroautophagy and chaperone-mediated autophagy, have been linked to different cancers. Overall, these studies build upon a steadfast trajectory that aims to solve the monumentally daunting challenge of finding a cure for many types of cancer by modulating autophagy either through inhibition or induction.
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19
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Understanding the Role of Autophagy in Cancer Formation and Progression Is a Real Opportunity to Treat and Cure Human Cancers. Cancers (Basel) 2021; 13:cancers13225622. [PMID: 34830777 PMCID: PMC8616104 DOI: 10.3390/cancers13225622] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/02/2021] [Accepted: 11/08/2021] [Indexed: 01/18/2023] Open
Abstract
Simple Summary The modulation of autophagy represents a potential therapeutic strategy for cancer. More than one hundred clinical trials have been conducted or are ongoing to explore the efficacy of autophagy modulators to reduce the tumor growth and potentiate the anti-cancer effects of conventional therapy. Despite this, the effective role of autophagy during tumor initiation, growth, and metastasis remains not well understood. Depending on the cancer type and stage of cancer, autophagy may have tumor suppressor properties as well as help cancer cells to proliferate and evade cancer therapy. The current review aims to summarize the current knowledge about the autophagy implications in cancer and report the therapeutic opportunities based on the modulation of the autophagy process. Abstract The malignant transformation of a cell produces the accumulation of several cellular adaptions. These changes determine variations in biological processes that are necessary for a cancerous cell to survive during stressful conditions. Autophagy is the main nutrient recycling and metabolic adaptor mechanism in eukaryotic cells, represents a continuous source of energy and biomolecules, and is fundamental to preserve the correct cellular homeostasis during unfavorable conditions. In recent decades, several findings demonstrate a close relationship between autophagy, malignant transformation, and cancer progression. The evidence suggests that autophagy in the cancer context has a bipolar role (it may act as a tumor suppressor and as a mechanism of cell survival for established tumors) and demonstrates that the targeting of autophagy may represent novel therapeutic opportunities. Accordingly, the modulation of autophagy has important clinical benefits in patients affected by diverse cancer types. Currently, about 30 clinical trials are actively investigating the efficacy of autophagy modulators to enhance the efficacy of cytotoxic chemotherapy treatments. A deeper understanding of the molecular pathways regulating autophagy in the cancer context will provide new ways to target autophagy for improving the therapeutic benefits. Herein, we describe how autophagy participates during malignant transformation and cancer progression, and we report the ultimate efforts to translate this knowledge into specific therapeutic approaches to treat and cure human cancers.
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20
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Bai L, Pfeifer T, Gross W, De La Torre C, Zhao S, Liu L, Schaefer M, Herr I. Establishment of Tumor Treating Fields Combined With Mild Hyperthermia as Novel Supporting Therapy for Pancreatic Cancer. Front Oncol 2021; 11:738801. [PMID: 34804927 PMCID: PMC8597267 DOI: 10.3389/fonc.2021.738801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 10/18/2021] [Indexed: 12/22/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with poor prognosis and limited therapeutic options. Alternating electrical fields with low intensity called "Tumor Treating Fields" (TTFields) are a new, non-invasive approach with almost no side effects and phase 3 trials are ongoing in advanced PDAC. We evaluated TTFields in combination with mild hyperthermia. Three established human PDAC cell lines and an immortalized pancreatic duct cell line were treated with TTFields and hyperthermia at 38.5°C, followed by microscopy, assays for MTT, migration, colony and sphere formation, RT-qPCR, FACS, Western blot, microarray and bioinformatics, and in silico analysis using the online databases GSEA, KEGG, Cytoscape-String, and Kaplan-Meier Plotter. Whereas TTFields and hyperthermia alone had weak effects, their combination strongly inhibited the viability of malignant, but not those of nonmalignant cells. Progression features and the cell cycle were impaired, and autophagy was induced. The identified target genes were key players in autophagy, the cell cycle and DNA repair. The expression profiles of part of these target genes were significantly involved in the survival of PDAC patients. In conclusion, the combination of TTFields with mild hyperthermia results in greater efficacy without increased toxicity and could be easily clinically approved as supporting therapy.
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Affiliation(s)
- Liping Bai
- Molecular OncoSurgery, Section Surgical Research, Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Tobias Pfeifer
- Molecular OncoSurgery, Section Surgical Research, Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Wolfgang Gross
- Molecular OncoSurgery, Section Surgical Research, Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Carolina De La Torre
- Medical Research Center, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Shuyang Zhao
- Department of Hematology, Oncology and Rheumatology, Internal Medicine V, University Hospital of Heidelberg, Heidelberg, Germany
| | - Li Liu
- Molecular OncoSurgery, Section Surgical Research, Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Michael Schaefer
- Molecular OncoSurgery, Section Surgical Research, Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Ingrid Herr
- Molecular OncoSurgery, Section Surgical Research, Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
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21
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Li J, Chen X, Kang R, Zeh H, Klionsky DJ, Tang D. Regulation and function of autophagy in pancreatic cancer. Autophagy 2021; 17:3275-3296. [PMID: 33161807 PMCID: PMC8632104 DOI: 10.1080/15548627.2020.1847462] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/26/2020] [Accepted: 11/02/2020] [Indexed: 12/12/2022] Open
Abstract
Oncogenic KRAS mutation-driven pancreatic ductal adenocarcinoma is currently the fourth-leading cause of cancer-related deaths in the United States. Macroautophagy (hereafter "autophagy") is one of the lysosome-dependent degradation systems that can remove abnormal proteins, damaged organelles, or invading pathogens by activating dynamic membrane structures (e.g., phagophores, autophagosomes, and autolysosomes). Impaired autophagy (including excessive activation and defects) is a pathological feature of human diseases, including pancreatic cancer. However, dysfunctional autophagy has many types and plays a complex role in pancreatic tumor biology, depending on various factors, such as tumor stage, microenvironment, immunometabolic state, and death signals. As a modulator connecting various cellular events, pharmacological targeting of nonselective autophagy may lead to both good and bad therapeutic effects. In contrast, targeting selective autophagy could reduce potential side effects of the drugs used. In this review, we describe the advances and challenges of autophagy in the development and therapy of pancreatic cancer.Abbreviations: AMPK: AMP-activated protein kinase; CQ: chloroquine; csc: cancer stem cells; DAMP: danger/damage-associated molecular pattern; EMT: epithelial-mesenchymal transition; lncRNA: long noncoding RNA; MIR: microRNA; PanIN: pancreatic intraepithelial neoplasia; PDAC: pancreatic ductal adenocarcinoma; PtdIns3K: phosphatidylinositol 3-kinase; SNARE: soluble NSF attachment protein receptor; UPS: ubiquitin-proteasome system.
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Affiliation(s)
- Jingbo Li
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Xin Chen
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Herbert Zeh
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Daniel J. Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
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22
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Chen S, Wang W, Tan HY, Lu Y, Li Z, Qu Y, Wang N, Wang D. Role of Autophagy in the Maintenance of Stemness in Adult Stem Cells: A Disease-Relevant Mechanism of Action. Front Cell Dev Biol 2021; 9:715200. [PMID: 34414192 PMCID: PMC8369482 DOI: 10.3389/fcell.2021.715200] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/15/2021] [Indexed: 01/07/2023] Open
Abstract
Autophagy is an intracellular scavenging mechanism induced to eliminate damaged, denatured, or senescent macromolecular substances and organelles in the body. The regulation of autophagy plays essential roles in the processes of cellular homeostasis and senescence. Dysregulated autophagy is a common feature of several human diseases, including cancers and neurodegenerative disorders. The initiation and development of these disorders have been shown to be associated with the maintenance of disease-specific stem cell compartments. In this review, we summarize recent advances in our understanding of the role of autophagy in the maintenance of stemness. Specifically, we focus on the intersection between autophagy and adult stem cells in the initiation and progression of specific diseases. Accordingly, this review highlights the role of autophagy in stemness maintenance from the perspective of disease-associated mechanisms, which may be fundamental to our understanding of the pathogeneses of human diseases and the development of effective therapies.
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Affiliation(s)
- Shanshan Chen
- School of Life Sciences, Jilin University, Changchun, China
| | - Wenqi Wang
- School of Life Sciences, Jilin University, Changchun, China
| | - Hor-Yue Tan
- Centre for Chinese Herbal Medicine Drug Development, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Yuanjun Lu
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Zhiping Li
- School of Life Sciences, Jilin University, Changchun, China
| | - Yidi Qu
- School of Life Sciences, Jilin University, Changchun, China
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun, China
- Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun, China
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23
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Estaras M, Gonzalez A. Modulation of cell physiology under hypoxia in pancreatic cancer. World J Gastroenterol 2021; 27:4582-4602. [PMID: 34366624 PMCID: PMC8326256 DOI: 10.3748/wjg.v27.i28.4582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/28/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
In solid tumors, the development of vasculature is, to some extent, slower than the proliferation of the different types of cells that form the tissue, both cancer and stroma cells. As a consequence, the oxygen availability is compromised and the tissue evolves toward a condition of hypoxia. The presence of hypoxia is variable depending on where the cells are localized, being less extreme at the periphery of the tumor and more severe in areas located deep within the tumor mass. Surprisingly, the cells do not die. Intracellular pathways that are critical for cell fate such as endoplasmic reticulum stress, apoptosis, autophagy, and others are all involved in cellular responses to the low oxygen availability and are orchestrated by hypoxia-inducible factor. Oxidative stress and inflammation are critical conditions that develop under hypoxia. Together with changes in cellular bioenergetics, all contribute to cell survival. Moreover, cell-to-cell interaction is established within the tumor such that cancer cells and the microenvironment maintain a bidirectional communication. Additionally, the release of extracellular vesicles, or exosomes, represents short and long loops that can convey important information regarding invasion and metastasis. As a result, the tumor grows and its malignancy increases. Currently, one of the most lethal tumors is pancreatic cancer. This paper reviews the most recent advances in the knowledge of how cells grow in a pancreatic tumor by adapting to hypoxia. Unmasking the physiological processes that help the tumor increase its size and their regulation will be of major relevance for the treatment of this deadly tumor.
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Affiliation(s)
- Matias Estaras
- Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, Caceres 10003, Spain
| | - Antonio Gonzalez
- Department of Physiology, Cell Biology and Communication Research Group, University of Extremadura, Caceres 10003, Spain
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24
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Talukdar S, Das SK, Emdad L, Fisher PB. Autophagy and senescence: Insights from normal and cancer stem cells. Adv Cancer Res 2021; 150:147-208. [PMID: 33858596 DOI: 10.1016/bs.acr.2021.01.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Autophagy is a fundamental cellular process, which allows cells to adapt to metabolic stress through the degradation and recycling of intracellular components to generate macromolecular precursors and produce energy. Autophagy is also critical in maintaining cellular/tissue homeostasis, as well preserving immunity and preventing human disease. Deregulation of autophagic processes is associated with cancer, neurodegeneration, muscle and heart disease, infectious diseases and aging. Research on a variety of stem cell types establish that autophagy plays critical roles in normal and cancer stem cell quiescence, activation, differentiation, and self-renewal. Considering its critical function in regulating the metabolic state of stem cells, autophagy plays a dual role in the regulation of normal and cancer stem cell senescence, and cellular responses to various therapeutic strategies. The relationships between autophagy, senescence, dormancy and apoptosis frequently focus on responses to various forms of stress. These are interrelated processes that profoundly affect normal and abnormal human physiology that require further elucidation in cancer stem cells. This review provides a current perspective on autophagy and senescence in both normal and cancer stem cells.
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Affiliation(s)
- Sarmistha Talukdar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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25
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López-Gil JC, Martin-Hijano L, Hermann PC, Sainz B. The CXCL12 Crossroads in Cancer Stem Cells and Their Niche. Cancers (Basel) 2021; 13:cancers13030469. [PMID: 33530455 PMCID: PMC7866198 DOI: 10.3390/cancers13030469] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/17/2021] [Accepted: 01/19/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary CXCL12 and its receptors have been extensively studied in cancer, including their influence on cancer stem cells (CSCs) and their niche. This intensive research has led to a better understanding of the crosstalk between CXCL12 and CSCs, which has aided in designing several drugs that are currently being tested in clinical trials. However, a comprehensive review has not been published to date. The aim of this review is to provide an overview on how CXCL12 axes are involved in the regulation and maintenance of CSCs, their presence and influence at different cellular levels within the CSC niche, and the current state-of-the-art of therapeutic approaches aimed to target the CXCL12 crossroads. Abstract Cancer stem cells (CSCs) are defined as a subpopulation of “stem”-like cells within the tumor with unique characteristics that allow them to maintain tumor growth, escape standard anti-tumor therapies and drive subsequent repopulation of the tumor. This is the result of their intrinsic “stem”-like features and the strong driving influence of the CSC niche, a subcompartment within the tumor microenvironment that includes a diverse group of cells focused on maintaining and supporting the CSC. CXCL12 is a chemokine that plays a crucial role in hematopoietic stem cell support and has been extensively reported to be involved in several cancer-related processes. In this review, we will provide the latest evidence about the interactions between CSC niche-derived CXCL12 and its receptors—CXCR4 and CXCR7—present on CSC populations across different tumor entities. The interactions facilitated by CXCL12/CXCR4/CXCR7 axes seem to be strongly linked to CSC “stem”-like features, tumor progression, and metastasis promotion. Altogether, this suggests a role for CXCL12 and its receptors in the maintenance of CSCs and the components of their niche. Moreover, we will also provide an update of the therapeutic options being currently tested to disrupt the CXCL12 axes in order to target, directly or indirectly, the CSC subpopulation.
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Affiliation(s)
- Juan Carlos López-Gil
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM, 28029 Madrid, Spain; (J.C.L.-G.); (L.M.-H.)
- Department of Biochemistry, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
- Chronic Diseases and Cancer, Area 3-Instituto Ramon y Cajal de Investigación Sanitaria (IRYCIS), 28029 Madrid, Spain
| | - Laura Martin-Hijano
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM, 28029 Madrid, Spain; (J.C.L.-G.); (L.M.-H.)
- Department of Biochemistry, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
- Chronic Diseases and Cancer, Area 3-Instituto Ramon y Cajal de Investigación Sanitaria (IRYCIS), 28029 Madrid, Spain
| | - Patrick C. Hermann
- Department of Internal Medicine I, Ulm University, 89081 Ulm, Germany
- Correspondence: (P.C.H.); (B.S.J.)
| | - Bruno Sainz
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM, 28029 Madrid, Spain; (J.C.L.-G.); (L.M.-H.)
- Department of Biochemistry, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
- Chronic Diseases and Cancer, Area 3-Instituto Ramon y Cajal de Investigación Sanitaria (IRYCIS), 28029 Madrid, Spain
- Correspondence: (P.C.H.); (B.S.J.)
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26
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Tao J, Yang G, Zhou W, Qiu J, Chen G, Luo W, Zhao F, You L, Zheng L, Zhang T, Zhao Y. Targeting hypoxic tumor microenvironment in pancreatic cancer. J Hematol Oncol 2021; 14:14. [PMID: 33436044 PMCID: PMC7805044 DOI: 10.1186/s13045-020-01030-w] [Citation(s) in RCA: 242] [Impact Index Per Article: 60.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/25/2020] [Indexed: 12/13/2022] Open
Abstract
Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.
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Affiliation(s)
- Jinxin Tao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Wenchuan Zhou
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, China
| | - Jiangdong Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Guangyu Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Wenhao Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Fangyu Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China. .,Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China.
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27
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Abbas S, Singh SK, Saxena AK, Tiwari S, Sharma LK, Tiwari M. Role of autophagy in regulation of glioma stem cells population during therapeutic stress. J Stem Cells Regen Med 2020; 16:80-89. [PMID: 33414584 PMCID: PMC7772813 DOI: 10.46582/jsrm.1602012] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022]
Abstract
Glioblastoma is highly recurrent and aggressive tumor with poor prognosis where existence of glioma stem cell (GSCs) population is well established. The GSCs display stem cell properties such as self-renewable, proliferation and therapeutic resistance which contribute to its role in tumor progression, metastasis and recurrence. Cancer stem cells (CSCs) can also be induced from non-stem cancer cells in response to radio/chemotherapy that further contribute to cancer relapse post therapy. Role of autophagy has been implicated in the existence of CSCs in different cancers; however, its role in GSCs is still unclear. Moreover, since autophagy is induced in response to various chemotherapeutic agents, it becomes imperative to understand the role of autophagy in therapy-induced pool of CSCs. Here, we investigated the role of autophagy in the maintenance of GSCs and temozolomide (TMZ)-induced therapeutic response. Glioblastoma cell lines (U87MG, LN229) were cultured as monolayer as well as GSC enriched tumorspheres and sub-spheroid population. Our results demonstrated that the tumorspheres maintained higher level of autophagy than the monolayer cells and inhibition of autophagy significantly reduced the percentage of GSCs and their self-renewal capacity. Further, TMZ at clinically relevant concentration resulted in an induction of survival autophagy in glioblastoma cells. We also observed that TMZ treatment significantly increased the expression of GSC markers, suggesting an increased pool of GSCs. Importantly, inhibition of autophagy prevented this TMZ-induced increased GSC population, suggesting a critical role for autophagy in therapy-induced generation of GSC pool. Overall, our findings revealed; i) higher levels of autophagy in GSCs; ii) TMZ induces protective autophagy and up-regulates pool of GSCs; and iii) inhibition of autophagy prevents TMZ-induced GSCs pool suggesting its role regulating GSC population in response to chemotherapy. Our study signifies a positive contribution of autophagy in survival of GSCs which implicates the use of autophagy inhibitors in a combinational approach to target TMZ-induced GSCs for developing effective therapeutic strategies. Further efforts are required to study the role of autophagy in therapy- induced GSC pool in other cancer types for its broad therapeutic implication.
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Affiliation(s)
- Sabiya Abbas
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences-Lucknow, (U.P.) India
| | - Suraj Kumar Singh
- Department of Pathology/Lab Medicine, All India Institute of Medical Sciences-Patna, Bihar, India
| | - Ajit Kumar Saxena
- Department of Pathology/Lab Medicine, All India Institute of Medical Sciences-Patna, Bihar, India
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences-Lucknow, (U.P.) India
| | - Lokendra Kumar Sharma
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences-Lucknow, (U.P.) India
| | - Meenakshi Tiwari
- Department of Pathology/Lab Medicine, All India Institute of Medical Sciences-Patna, Bihar, India
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28
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da Silva Filho AF, de Sousa LM, Consonni SR, da Rocha Pitta MG, Carvalho HF, de Melo Rêgo MJB. Galectin-3 Expression in Pancreatic Cell Lines Under Distinct Autophagy-Inducing Stimulus. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2020; 26:1187-1197. [PMID: 33107424 DOI: 10.1017/s1431927620024526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Hypoxia and nutrient deprivation are responsible for inducing malignant behavior in neoplastic cells. In these conditions, metabolic stress leads the cells to enhance their autophagic flux and to activate key molecules for homeostasis maintenance. Galectin-3 (Gal-3) is upregulated in pancreatic cancer and it is activated under the hypoxic atmosphere. We aimed to analyze the most effective autophagic-inducing conditions in pancreatic ductal adenocarcinoma cells and the effect exerted under these conditions in association with hypoxia on the Gal-3 expression. Gal-3 and the microtubule-associated protein light chain 3 beta (LC3) were accessed through western blot and immunofluorescence. Degradative vacuole quantification was analyzed by transmission electronic microscopy, and inhibition of Gal-3 was performed using siRNA. According to the analyses, the most effective conditions in the inducement of autophagy for PANC-1 and MIA PaCa-2 cells were nutritional deprivation and complete amino acid/glucose deprivation, respectively. PANC-1 cells presented higher Gal-3 when they were submitted to 24 h of nutritional deprivation alone and simultaneously nutritional and oxygen deprivation. Inhibition of Gal-3 causes a decrease of LC3 levels in all experimental conditions. These results confirm that Gal-3 is modulated by microenvironment factors and the possibility of Gal-3 participating in an adaptive response from PDAC cells to extreme conditions.
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Affiliation(s)
- Antônio Felix da Silva Filho
- Immunomodulation and New Therapy Approaches Laboratory (LINAT), Biochemistry Department, Federal University of Pernambuco (UFPE), Cidade Universitária, Recife, Pernambuco50670-901, Brazil
| | - Lizandra Maia de Sousa
- Laboratory of Cytochemistry and Immunocytochemistry, Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), Cidade Universitária Zeferino Vaz, Campinas, São Paulo13083-970, Brazil
| | - Silvio Roberto Consonni
- Laboratory of Cytochemistry and Immunocytochemistry, Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), Cidade Universitária Zeferino Vaz, Campinas, São Paulo13083-970, Brazil
| | - Maira Galdino da Rocha Pitta
- Immunomodulation and New Therapy Approaches Laboratory (LINAT), Biochemistry Department, Federal University of Pernambuco (UFPE), Cidade Universitária, Recife, Pernambuco50670-901, Brazil
| | - Hernandes Faustino Carvalho
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Cidade Universitária Zeferino Vaz, Campinas, São Paulo13083-970, Brazil
| | - Moacyr Jesus Barreto de Melo Rêgo
- Immunomodulation and New Therapy Approaches Laboratory (LINAT), Biochemistry Department, Federal University of Pernambuco (UFPE), Cidade Universitária, Recife, Pernambuco50670-901, Brazil
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Therapeutic Innovation Research Center- Suelly Galdino (NUPIT-SG), Biochemistry Department, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, Pernambuco50670-901, Brazil
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29
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Praharaj PP, Panigrahi DP, Bhol CS, Patra S, Mishra SR, Mahapatra KK, Behera BP, Singh A, Patil S, Bhutia SK. Mitochondrial rewiring through mitophagy and mitochondrial biogenesis in cancer stem cells: A potential target for anti-CSC cancer therapy. Cancer Lett 2020; 498:217-228. [PMID: 33186655 DOI: 10.1016/j.canlet.2020.10.036] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/12/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023]
Abstract
Cancer stem cells (CSCs) are distinct subpopulations of cancer cells with stem cell-like abilities and are more resilient to chemotherapy, causing tumor relapse. Mitophagy, a selective form of autophagy, removes damaged unwanted mitochondria from cells through a lysosome-based degradation pathway to maintain cellular homeostasis. CSCs use mitophagy as a chief survival response mechanism for their growth, propagation, and tumorigenic ability. Mitochondrial biogenesis is a crucial cellular event replacing damaged mitochondria through the coordinated regulation of several transcription factors to achieve the bioenergetic demands of the cell. Because of the high mitochondrial content in CSCs, mitochondrial biogenesis is an interesting target to address the resistance mechanisms of anti-CSC therapy. However, to what extent both mitophagy and mitochondrial biogenesis are vital in promoting stemness, metabolic reprogramming, and drug resistance in CSCs has yet to be established. Therefore, in this review, we focus on understanding the interesting aspects of mitochondrial rewiring that involve mitophagy and mitochondrial biogenesis in CSCs. We also discuss their coordinated regulation in the elimination of CSCs, with respect to stemness and differentiation of the CSC phenotype, and the different aspects of tumorigenesis such as cancer initiation, progression, resistance, and tumor relapse. Finally, we address several other unanswered questions relating to targeted anti-CSC cancer therapy, which improves patient survival.
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Affiliation(s)
- Prakash Priyadarshi Praharaj
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Debasna Pritimanjari Panigrahi
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Chandra Sekhar Bhol
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Soumya Ranjan Mishra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Kewal Kumar Mahapatra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Bishnu Prasad Behera
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Amruta Singh
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Saudi Arabia
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India.
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30
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Najafzadeh B, Asadzadeh Z, Motafakker Azad R, Mokhtarzadeh A, Baghbanzadeh A, Alemohammad H, Abdoli Shadbad M, Vasefifar P, Najafi S, Baradaran B. The oncogenic potential of NANOG: An important cancer induction mediator. J Cell Physiol 2020; 236:2443-2458. [PMID: 32960465 DOI: 10.1002/jcp.30063] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/02/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022]
Abstract
Cancer stem cells (CSCs) are a unique population in the tumor, but they only comprise 2%-5% of the tumor bulk. Although CSCs share several features with embryonic stem cells, CSCs can give rise to the tumor cells. CSCs overexpress embryonic transcription factor NANOG, which is downregulated in differentiated tissues. This transcription factor confers CSC's stemness, unlimited self-renewal, metastasis, invasiveness, angiogenesis, and drug-resistance with the assistance of WNT, OCT4, SOX2, Hedgehog, BMI-1, and other complexes. NANOG facilitates CSCs development via multiple pathways, like angiogenesis and lessening E-cadherin expression levels, which paves the road for metastasis. Moreover, NANOG represses apoptosis and leads to drug-resistance. This review aims to highlight the pivotal role of NANOG and the pertained pathways in CSCs. Also, this current study intends to demonstrate that targeting NANOG can dimmish the CSCs, sensitize the tumor to chemotherapy, and eradicate the cancer cells.
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Affiliation(s)
- Basira Najafzadeh
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajar Alemohammad
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Parisa Vasefifar
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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31
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Qureshi-Baig K, Kuhn D, Viry E, Pozdeev VI, Schmitz M, Rodriguez F, Ullmann P, Koncina E, Nurmik M, Frasquilho S, Nazarov PV, Zuegel N, Boulmont M, Karapetyan Y, Antunes L, Val D, Mittelbronn M, Janji B, Haan S, Letellier E. Hypoxia-induced autophagy drives colorectal cancer initiation and progression by activating the PRKC/PKC-EZR (ezrin) pathway. Autophagy 2020; 16:1436-1452. [PMID: 31775562 PMCID: PMC7469473 DOI: 10.1080/15548627.2019.1687213] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 10/11/2019] [Accepted: 10/21/2019] [Indexed: 12/20/2022] Open
Abstract
In solid tumors, cancer stem cells (CSCs) or tumor-initiating cells (TICs) are often found in hypoxic niches. Nevertheless, the influence of hypoxia on TICs is poorly understood. Using previously established, TIC-enrichedpatient-derived colorectal cancer (CRC) cultures, we show that hypoxia increases the self-renewal capacity of TICs while inducing proliferation arrest in their more differentiated counterpart cultures. Gene expression data revealed macroautophagy/autophagy as one of the major pathways induced by hypoxia in TICs. Interestingly, hypoxia-induced autophagy was found to induce phosphorylation of EZR (ezrin) at Thr567 residue, which could be reversed by knocking down ATG5, BNIP3, BNIP3L, or BECN1. Furthermore, we identified PRKCA/PKCα as a potential kinase involved in hypoxia-induced autophagy-mediated TIC self-renewal. Genetic targeting of autophagy or pharmacological inhibition of PRKC/PKC and EZR resulted in decreased tumor-initiating potential of TICs. In addition, we observed significantly reduced in vivo tumor initiation and growth after a stable knockdown of ATG5. Analysis of human CRC samples showed that p-EZR is often present in TICs located in the hypoxic and autophagic regions of the tumor. Altogether, our results establish the hypoxia-autophagy-PKC-EZR signaling axis as a novel regulatory mechanism of TIC self-renewal and CRC progression. Autophagy inhibition might thus represent a promising therapeutic strategy for cancer patients. ABBREVIATIONS ATG: autophagy related; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CQ: chloroquine; CSC: cancer stem cells; CRC: colorectal cancer; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PRKC/PKC: protein kinase C; SQSTM1/p62: sequestosome 1; TICs: tumor-initiating cells.
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Affiliation(s)
- Komal Qureshi-Baig
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Diana Kuhn
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Elodie Viry
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Laboratory of Experimental Cancer Research, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Vitaly I. Pozdeev
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Martine Schmitz
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Fabien Rodriguez
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Pit Ullmann
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Eric Koncina
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Martin Nurmik
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | | | - Petr V. Nazarov
- Proteome and Genome Research Unit, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Nikolaus Zuegel
- Department of Surgery, Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg
| | - Marc Boulmont
- Department of Surgery, Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg
| | | | - Laurent Antunes
- Integrated Biobank of Luxembourg, Dudelange, Luxembourg
- Department of Anatomic and Molecular Pathology, Laboratoire National de Santé (LNS), Dudelange, Luxembourg
| | - Daniel Val
- Department of Anatomic and Molecular Pathology, Laboratoire National de Santé (LNS), Dudelange, Luxembourg
| | - Michel Mittelbronn
- Department of Anatomic and Molecular Pathology, Laboratoire National de Santé (LNS), Dudelange, Luxembourg
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
- NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Strassen, Luxembourg
- Luxembourg Centre of Neuropathology (LCNP), Dudelange, Luxembourg
| | - Bassam Janji
- Laboratory of Experimental Cancer Research, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Serge Haan
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Elisabeth Letellier
- Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
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Koifman G, Aloni-Grinstein R, Rotter V. p53 balances between tissue hierarchy and anarchy. J Mol Cell Biol 2020; 11:553-563. [PMID: 30925590 PMCID: PMC6735948 DOI: 10.1093/jmcb/mjz022] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 01/17/2019] [Accepted: 02/13/2019] [Indexed: 02/07/2023] Open
Abstract
Normal tissues are organized in a hierarchical model, whereas at the apex of these hierarchies reside stem cells (SCs) capable of self-renewal and of producing differentiated cellular progenies, leading to normal development and homeostasis. Alike, tumors are organized in a hierarchical manner, with cancer SCs residing at the apex, contributing to the development and nourishment of tumors. p53, the well-known ‘guardian of the genome’, possesses various roles in embryonic development as well as in adult SC life and serves as the ‘guardian of tissue hierarchy’. Moreover, p53 serves as a barrier for dedifferentiation and reprogramming by constraining the cells to a somatic state and preventing their conversion to SCs. On the contrary, the mutant forms of p53 that lost their tumor suppressor activity and gain oncogenic functions serve as ‘inducers of tissue anarchy’ and promote cancer development. In this review, we discuss these two sides of the p53 token that sentence a tissue either to an ordered hierarchy and life or to anarchy and death. A better understanding of these processes may open new horizons for the development of new cancer therapies.
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Affiliation(s)
- Gabriela Koifman
- Department of Molecular Cell Biology, the Weizmann Institute of Science, Rehovot, Israel
| | - Ronit Aloni-Grinstein
- Department of Molecular Cell Biology, the Weizmann Institute of Science, Rehovot, Israel.,Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel
| | - Varda Rotter
- Department of Molecular Cell Biology, the Weizmann Institute of Science, Rehovot, Israel
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Mandhair HK, Arambasic M, Novak U, Radpour R. Molecular modulation of autophagy: New venture to target resistant cancer stem cells. World J Stem Cells 2020; 12:303-322. [PMID: 32547680 PMCID: PMC7280868 DOI: 10.4252/wjsc.v12.i5.303] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/19/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a highly regulated catabolic process in which superfluous, damaged organelles and other cytoplasmic constituents are delivered to the lysosome for clearance and the generation of macromolecule substrates during basal or stressed conditions. Autophagy is a bimodal process with a context dependent role in the initiation and the development of cancers. For instance, autophagy provides an adaptive response to cancer stem cells to survive metabolic stresses, by influencing disease propagation via modulation of essential signaling pathways or by promoting resistance to chemotherapeutics. Autophagy has been implicated in a cross talk with apoptosis. Understanding the complex interactions provides an opportunity to improve cancer therapy and the clinical outcome for the cancer patients. In this review, we provide a comprehensive view on the current knowledge on autophagy and its role in cancer cells with a particular focus on cancer stem cell homeostasis.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Miroslav Arambasic
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland.
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Yamasaki A, Yanai K, Onishi H. Hypoxia and pancreatic ductal adenocarcinoma. Cancer Lett 2020; 484:9-15. [PMID: 32380129 DOI: 10.1016/j.canlet.2020.04.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 03/13/2020] [Accepted: 04/09/2020] [Indexed: 12/12/2022]
Abstract
Chemotherapy and immunotherapy for pancreatic ductal adenocarcinoma (PDAC) have limited success. One reason for this is thought to be the cancer microenvironment surrounding PDAC. Hypoxia is a feature of the cancer microenvironment. Under hypoxia, different various molecules and signaling pathways are activated compared with normoxia. To develop a new effective therapeutic strategy for PDAC, we need to target these hypoxic conditions to overcome PDAC. To inhibit the malignant phenotype, the cellular changes that occur under hypoxia should be elucidated. Various molecules and signaling that are activated by hypoxia may contribute to the induction of malignant phenotypes of PDAC such as proliferation, invasion, tumorigenesis, chemosensitivity, and autophagy. If we can develop therapeutic approaches to target one of these molecules or signaling pathways, we may proceed to the next therapeutic step of successfully treating refractory PDAC.
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Affiliation(s)
- Akio Yamasaki
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kosuke Yanai
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideya Onishi
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Görgülü K, Diakopoulos KN, Kaya-Aksoy E, Ciecielski KJ, Ai J, Lesina M, Algül H. The Role of Autophagy in Pancreatic Cancer: From Bench to the Dark Bedside. Cells 2020; 9:E1063. [PMID: 32344698 PMCID: PMC7226443 DOI: 10.3390/cells9041063] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 02/27/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is one of the deadliest cancer types urgently requiring effective therapeutic strategies. Autophagy occurs in several compartments of pancreatic cancer tissue including cancer cells, cancer associated fibroblasts, and immune cells where it can be subjected to a multitude of stimulatory and inhibitory signals fine-tuning its activity. Therefore, the effects of autophagy on pancreatic carcinogenesis and progression differ in a stage and context dependent manner. In the initiation stage autophagy hinders development of preneoplastic lesions; in the progression stage however, autophagy promotes tumor growth. This double-edged action of autophagy makes it a hard therapeutic target. Indeed, autophagy inhibitors have not yet shown survival improvements in clinical trials, indicating a need for better evaluation of existing results and smarter targeting techniques. Clearly, the role of autophagy in pancreatic cancer is complex and many aspects have to be considered when moving from the bench to the bedside.
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Affiliation(s)
- Kıvanç Görgülü
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
| | - Kalliope N. Diakopoulos
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
| | - Ezgi Kaya-Aksoy
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
| | - Katrin J. Ciecielski
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
| | - Jiaoyu Ai
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Marina Lesina
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
| | - Hana Algül
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
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Wang K, He H. Pancreatic Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1296:243-257. [PMID: 34185297 DOI: 10.1007/978-3-030-59038-3_15] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The pancreatic ductal adenocarcinoma (PDAC) microenvironment is a diverse and complex milieu of immune, stromal, and tumor cells and is characterized by a dense stroma, which mediates the interaction between the tumor and the immune system within the tumor microenvironment (TME). The interaction between stromal and tumor cells signals and shapes the immune infiltration of TME. The desmoplastic compartment contains infiltrated immune cells including tumor-associated macrophages (TAMs) and large numbers of fibroblasts/myofibroblasts dominated by pancreatic stellate cells (PSCs) which contribute to fibrosis. The highly fibrotic stroma with its extensive infiltration of immunosuppressive cells forms the major component of the pro-tumorigenic microenvironment (Laklai et al. Nat Med 22:497-505, 2016, Zhu et al. Cancer Res 74:5057-5069, 2014) provides a barrier to the delivery of cytotoxic agents and limits T-cell access to tumor cells (Feig et al. Proc Natl Acad Sci USA 110:20212-20217, 2013, Provenzano et al Cancer Cell 21:418-429, 2012). Activated PSCs reduced infiltration of cytotoxic T cells to the juxtatumoral stroma (immediately adjacent to the tumor epithelial cells) of PDAC (Ene-Obong et al. Gastroenterology 145:1121-1132, 2013). M1 macrophages activate an immune response against tumor, but M2 macrophages are involved in immunosuppression promoting tumor progression (Noy and Pollard Immunity 41:49-61, 2014, Ruffell et al. Trends Immunol 33:119-126, 2012). The desmoplastic stroma is reported to protect tumor cells against chemotherapies, promoting their proliferation and migration. However, experimental depletion of the desmoplastic stroma has led to more aggressive cancers in animal studies (Nielsen et al. World J Gastroenterol 22:2678-2700, 2016). Hence reprogramming rather than simple depletion of the PDAC stroma has the potential for developing new therapeutic strategies for PC treatment. Modulation of PSCs/fibrosis and immune infiltration/inflammation composes the major aspects of TME reprogramming.
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Affiliation(s)
- Kai Wang
- Department of Surgery, University of Melbourne, Austin Health, Heidelberg, VIC, Australia
| | - Hong He
- Department of Surgery, University of Melbourne, Austin Health, Heidelberg, VIC, Australia.
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New M, Tooze S. The Role of Autophagy in Pancreatic Cancer-Recent Advances. BIOLOGY 2019; 9:E7. [PMID: 31905604 PMCID: PMC7169408 DOI: 10.3390/biology9010007] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/23/2019] [Accepted: 12/26/2019] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with a 5-year survival rate of only 9%, despite ongoing efforts to improve treatment. This dismal prognosis is due to the difficulty of early stage diagnosis, drug resistance, and likelihood of metastasis development. It is therefore of great importance to identify appropriate therapeutic targets and gain a greater understanding of PDAC biology. Autophagy is a membrane-mediated degradation and recycling mechanism, which is crucial for cell homeostasis. There is evidence for both a tumor-suppressive and a tumor-promoting role of autophagy in cancer, and this is likely context dependent. Within PDAC, a large body of evidence points towards autophagy being required for tumor survival and metabolism. In this review, we describe the recent advances in the understanding of the role and regulation of autophagy in PDAC.
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Affiliation(s)
| | - Sharon Tooze
- Molecular Cell Biology of Autophagy Laboratory, The Francis Crick Institute, London NW1 1AT, UK;
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Martinez-Ciarpaglini C, Fernandez-Sellers C, Tarazona N, Roselló S, Huerta M, Roda D, Mongort C, Ferrández A, Navarro S, Cervantes A. Improving tumour budding evaluation in colon cancer by extending the assessment area in colectomy specimens. Histopathology 2019; 75:517-525. [PMID: 31081121 DOI: 10.1111/his.13900] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 05/09/2019] [Indexed: 01/02/2023]
Abstract
AIMS It is recommended that tumour budding in colon cancer be counted on haematoxylin and eosin-stained sections in a hotspot area of 0.785 mm2 with a ×20 microscope objective. However, tumour buds may be difficult to visualise on haematoxylin and eosin-stained sections, and counting in such a limited area may result in overestimation in cases with focal budding. The aim of this study was to assess the contributions of various factors to improving tumour budding risk stratification: increasing the number of fields counted, using cytokeratin immunostaining, and recording proliferation, the apoptotic index and the emperipoletic index in tumour buds. METHODS AND RESULTS We created an exploratory series composed of 172 cases of colon cancer in all stages, and we analysed the survival probability in a second cohort of 158 stage I-II patients. According to our results, counting of budding in 10 fields was the only factor that was significantly correlated with disease-free survival probability in stage I-II patients [hazard ratio (HR) for high versus low grade of 7.64, 95% confidence interval (CI) 5.54-27.92, P = 0.01; HR for intermediate versus low grade of 3.02, 95% CI 1.54-26.72, P = 0.04). Emperipolesis was frequently observed in tumour buds, whereas the mitotic index and the apoptotic index were extremely low. Although cytokeratin immunostaining increased interobserver concordance, it did not improve the accuracy of tumour budding grading. CONCLUSIONS According to our results, counting in 10 fields significantly enhanced the budding grade risk stratification in colon cancer patients, and cytokeratin immunostaining could be reserved as a complementary technique for challenging cases with an inflammatory infiltrate and/or striking fibrosis.
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Affiliation(s)
| | | | - Noelia Tarazona
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain
| | - Susana Roselló
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain
| | - Marisol Huerta
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain
| | - Desamparados Roda
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain
| | - Cristina Mongort
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain
| | - Antonio Ferrández
- Department of Pathology, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Samuel Navarro
- Department of Pathology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain
| | - Andres Cervantes
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain
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Zhao Z, Bai S, Wang R, Xiong S, Li Y, Wang X, Chen W, Cheng B. Cancer-associated fibroblasts endow stem-like qualities to liver cancer cells by modulating autophagy. Cancer Manag Res 2019; 11:5737-5744. [PMID: 31296998 PMCID: PMC6598753 DOI: 10.2147/cmar.s197634] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 05/29/2019] [Indexed: 12/24/2022] Open
Abstract
Purpose Both cancer-associated fibroblasts (CAFs) and liver cancer stem cells (LCSCs) play an important part in the tumorigenesis, development and metastasis of hepatocellular carcinoma (HCC). Moreover, the stem-like properties in HCC cells could be promoted by CAFs. However, the mechanism remains largely unknown. Patients and methods We used conditioned medium (CM) of CAFs to culture Huh7 cells. Stemness of the cells was then examined mainly by sphere formation assay while stemness-associated genes including Nanog, Sox2 and Oct4 were measured by Western blotting. Immunofluorescence staining, Transmission Electron Microscope as well as Western blotting were performed to detect the level of autophagy in Huh7 cells. Results Increased level of stemness and autophagy was observed in HCC cells cultured in CAFs-CM compared to the control group. Activation of CAFs-induced autophagic flux could be inhibited by Chloroquine (CQ), which can accumulate LC3-II protein and increase punctate distribution of LC3 localization. Treatment of HCC cells with CQ effectively reversed the CAF-induced stemness, invasion, and metastasis ability in these cells. In vivo, Huh7 cells inoculated together with CAFs developed significantly larger tumors than Huh7 cells injected alone. Moreover, blockage of autophagy in Huh7 cells by CQ greatly reduced the growth of xenografted tumors of Huh7 cells combined with CAFs. Conclusion These results reveal that CAFs are capable of promoting stemness and metastasis of HCC cells and blocking autophagy could markedly attenuate the stemness enhanced by CAFs, suggesting that targeting autophagy in HCC could be an effective strategy in HCC treatment.
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Affiliation(s)
- Zhenxiong Zhao
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Shuya Bai
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Ronghua Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Si Xiong
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Yawen Li
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Xiju Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Wei Chen
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Bin Cheng
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
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Daniel SK, Sullivan KM, Labadie KP, Pillarisetty VG. Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma. Clin Transl Med 2019; 8:10. [PMID: 30931508 PMCID: PMC6441665 DOI: 10.1186/s40169-019-0226-9] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 03/09/2019] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with limited response to cytotoxic chemoradiotherapy, as well as newer immunotherapies. The PDA tumor microenvironment contains infiltrating immune cells including cytotoxic T cells; however, there is an overall immunosuppressive milieu. Hypoxia is a known element of the solid tumor microenvironment and may promote tumor survival. Through various mechanisms including, but not limited to, those mediated by HIF-1α, hypoxia also leads to increased tumor proliferation and metabolic changes. Furthermore, epithelial to mesenchymal transition is promoted through several pathways, including NOTCH and c-MET, regulated by hypoxia. Hypoxia-promoted changes also contribute to the immunosuppressive phenotype seen in many different cell types within the microenvironment and thereby may inhibit an effective immune system response to PDA. Pancreatic stellate cells (PSCs) and myofibroblasts appear to contribute to the recruitment of myeloid derived suppressor cells (MDSCs) and B cells in PDA via cytokines increased due to hypoxia. PSCs also increase collagen secretion in response to HIF-1α, which promotes a fibrotic stroma that alters T cell homing and migration. In hypoxic environments, B cells contribute to cytotoxic T cell exhaustion and produce chemokines to attract more immunosuppressive regulatory T cells. MDSCs inhibit T cell metabolism by hoarding key amino acids, modulate T cell homing by cleaving L-selectin, and prevent T cell activation by increasing PD-L1 expression. Immunosuppressive M2 phenotype macrophages promote T cell anergy via increased nitric oxide (NO) and decreased arginine in hypoxia. Increased numbers of regulatory T cells are seen in hypoxia which prevent effector T cell activation through cytokine production and increased CTLA-4. Effective immunotherapy for pancreatic adenocarcinoma and other solid tumors will need to help counteract the immunosuppressive nature of hypoxia-induced changes in the tumor microenvironment. Promising studies will look at combination therapies involving checkpoint inhibitors, chemokine inhibitors, and possible targeting of hypoxia. While no model is perfect, assuring that models incorporate the effects of hypoxia on cancer cells, stromal cells, and effector immune cells will be crucial in developing successful therapies.
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Affiliation(s)
- S K Daniel
- Department of Surgery, University of Washington, Seattle, USA
| | - K M Sullivan
- Department of Surgery, University of Washington, Seattle, USA
| | - K P Labadie
- Department of Surgery, University of Washington, Seattle, USA
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Smith AG, Macleod KF. Autophagy, cancer stem cells and drug resistance. J Pathol 2019; 247:708-718. [PMID: 30570140 DOI: 10.1002/path.5222] [Citation(s) in RCA: 270] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 12/10/2018] [Accepted: 12/14/2018] [Indexed: 12/13/2022]
Abstract
Autophagy is a cellular survival mechanism that is induced by cancer therapy, among other stresses, and frequently contributes to cancer cell survival during long periods of dormancy and the eventual outgrowth of metastatic disease. Autophagy degrades large cellular structures that, once broken down, contribute to cellular survival through the recycling of their constituent metabolites. However, the extent to which this fuel function of autophagy is key to its role in promoting stemness, dormancy and drug resistance remains to be determined. Other roles for autophagy in determining cell fate more directly through targeted degradation of key transcription factors, such as p53 and FoxO3A, or by enforcing a reversible quiescent growth arrest, are discussed in this review. This review also highlights the need to parse out the roles of different forms of selective autophagy in stemness, CD44 expression and dormancy that, for example, are increasingly being attributed explicitly to mitophagy. The clinical relevance of this work and how an increased understanding of functions of autophagy in stemness, dormancy and drug resistance could be manipulated for increased therapeutic benefit, including eliminating minimal residual disease and preventing metastasis, are discussed. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Alexandra G Smith
- The Ben May Department for Cancer Research, The Gordon Center for Integrative Sciences, The University of Chicago, Chicago, IL, USA.,The Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA.,Multi-disciplinary Training Grant in Cancer Research, University of Chicago, Chicago, IL, USA
| | - Kay F Macleod
- The Ben May Department for Cancer Research, The Gordon Center for Integrative Sciences, The University of Chicago, Chicago, IL, USA.,The Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA.,Multi-disciplinary Training Grant in Cancer Research, University of Chicago, Chicago, IL, USA
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42
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Da Ros M, De Gregorio V, Iorio AL, Giunti L, Guidi M, de Martino M, Genitori L, Sardi I. Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier. Int J Mol Sci 2018; 19:ijms19102879. [PMID: 30248992 PMCID: PMC6213072 DOI: 10.3390/ijms19102879] [Citation(s) in RCA: 147] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 09/19/2018] [Accepted: 09/20/2018] [Indexed: 12/27/2022] Open
Abstract
For glioblastoma, the tumor microenvironment (TME) is pivotal to support tumor progression and therapeutic resistance. TME consists of several types of stromal, endothelial and immune cells, which are recruited by cancer stem cells (CSCs) to influence CSC phenotype and behavior. TME also promotes the establishment of specific conditions such as hypoxia and acidosis, which play a critical role in glioblastoma chemoresistance, interfering with angiogenesis, apoptosis, DNA repair, oxidative stress, immune escape, expression and activity of multi-drug resistance (MDR)-related genes. Finally, the blood brain barrier (BBB), which insulates the brain microenvironment from the blood, is strongly linked to the drug-resistant phenotype of glioblastoma, being a major physical and physiological hurdle for the delivery of chemotherapy agents into the brain. Here, we review the features of the glioblastoma microenvironment, focusing on their involvement in the phenomenon of chemoresistance; we also summarize recent advances in generating systems to modulate or bypass the BBB for drug delivery into the brain. Genetic aspects associated with glioblastoma chemoresistance and current immune-based strategies, such as checkpoint inhibitor therapy, are described too.
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Affiliation(s)
- Martina Da Ros
- Neuro-oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital, Florence, 50139, Italy.
| | - Veronica De Gregorio
- Neuro-oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital, Florence, 50139, Italy.
| | - Anna Lisa Iorio
- Neuro-oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital, Florence, 50139, Italy.
| | - Laura Giunti
- Medical Genetics Unit, Meyer Children's University Hospital, 50139 Florence, Italy.
| | - Milena Guidi
- Neuro-oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital, Florence, 50139, Italy.
| | - Maurizio de Martino
- Director Post Graduate Pediatric School University of Florence, Director Meyer Health Campus, Florence, 50139, Italy.
| | - Lorenzo Genitori
- Neurosurgery Unit, Department of Neurosciences, Meyer Children's Hospital, Florence, 50139, Italy.
| | - Iacopo Sardi
- Neuro-oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital, Florence, 50139, Italy.
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43
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High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling. Cell Death Dis 2018; 9:896. [PMID: 30166520 PMCID: PMC6117306 DOI: 10.1038/s41419-018-0903-4] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 07/13/2018] [Accepted: 07/19/2018] [Indexed: 12/22/2022]
Abstract
Aldehyde dehydrogenase 1A1 (ALDH1A1) is one of cancer stem cell (CSC) markers, and high ALDH1 expression has been related to drug resistance and facilitated tumor growth. In this study, we investigated the potential involvement of nuclear factor erythroid 2-like 2 (NFE2L2/NRF2) in CSC-like properties of ALDH-high ovarian CSCs. Our experimental system, ALDH1A1-high (ALDH-H) subpopulation, was isolated and stabilized using doxorubicin-resistant ovarian cancer A2780 cells. ALDH-H exerted CSC-like properties such as drug resistance, colony/sphere formation, and enhanced tumor growth along with high levels of CSCs markers compared to ALDH1A1-low (ALDH-L). Levels of NRF2 and subsequent target genes substantially increased in ALDH-H cells, and the increase in ALDH1A1 and p62 was associated with NRF2 upregulation. ALDH1A1-silencing blocked increases in NRF2, drug efflux transporters, and p62, along with CSC markers in ALDH-H cells. The inhibition of p62, which was elevated in ALDH-H, suppressed NRF2 activation. High NRF2 level was confirmed in the ALDH1-high subpopulation from colon cancer HCT116 cells. The functional implication of NRF2 activation in ovarian CSCs was verified by two experimental approaches. First, CSC-like properties such as high CSC markers, chemoresistance, colony/sphere formation, and tumor growth were significantly inhibited by NRF2-silencing in ALDH-H cells. Second, all-trans retinoic acid (ATRA) suppressed ALDH1 expression, inhibiting NRF2 activation, which led to the attenuation of CSC-like properties in ALDH-H cells but not in ALDH-L cells. These results provide insight into the molecular basis of the ALDH1A1-mediated development of CSC-like properties such as stress/treatment resistance, and further suggest the therapeutic potential of ATRA in ALDH-high ovarian CSCs.
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44
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Peña-Oyarzun D, Bravo-Sagua R, Diaz-Vega A, Aleman L, Chiong M, Garcia L, Bambs C, Troncoso R, Cifuentes M, Morselli E, Ferreccio C, Quest AFG, Criollo A, Lavandero S. Autophagy and oxidative stress in non-communicable diseases: A matter of the inflammatory state? Free Radic Biol Med 2018; 124:61-78. [PMID: 29859344 DOI: 10.1016/j.freeradbiomed.2018.05.084] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 05/22/2018] [Accepted: 05/28/2018] [Indexed: 12/11/2022]
Abstract
Non-communicable diseases (NCDs), also known as chronic diseases, are long-lasting conditions that affect millions of people around the world. Different factors contribute to their genesis and progression; however they share common features, which are critical for the development of novel therapeutic strategies. A persistently altered inflammatory response is typically observed in many NCDs together with redox imbalance. Additionally, dysregulated proteostasis, mainly derived as a consequence of compromised autophagy, is a common feature of several chronic diseases. In this review, we discuss the crosstalk among inflammation, autophagy and oxidative stress, and how they participate in the progression of chronic diseases such as cancer, cardiovascular diseases, obesity and type II diabetes mellitus.
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Affiliation(s)
- Daniel Peña-Oyarzun
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile
| | - Roberto Bravo-Sagua
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
| | - Alexis Diaz-Vega
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Larissa Aleman
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Mario Chiong
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Lorena Garcia
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Claudia Bambs
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Salud Pública, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rodrigo Troncoso
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
| | - Mariana Cifuentes
- Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Eugenia Morselli
- Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catterina Ferreccio
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Salud Pública, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Andrew F G Quest
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Alfredo Criollo
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile.
| | - Sergio Lavandero
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Cardiology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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45
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Affiliation(s)
- Amir Barzegar Behrooz
- Department of Biochemistry, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Malaysia
| | - Amir Syahir
- Department of Biochemistry, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Malaysia
| | - Syahida Ahmad
- Department of Biochemistry, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Malaysia
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46
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Lleonart ME, Abad E, Graifer D, Lyakhovich A. Reactive Oxygen Species-Mediated Autophagy Defines the Fate of Cancer Stem Cells. Antioxid Redox Signal 2018; 28:1066-1079. [PMID: 28683561 DOI: 10.1089/ars.2017.7223] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Significance: A fraction of tumorigenic cells, also known as tumor initiating or cancer stem cells (CSCs), is thought to drive tumor growth, metastasis, and chemoresistance. However, little is known regarding mechanisms that convey relevant pathways contributing to their self-renewal, proliferation, and differentiation abilities. Recent Advances: Recent works on CSCs provide evidence on the role of redox disruption and regulation of autophagic flux. This has been linked to increased DNA repair capacity and chemoresistance. Critical Issues: The current review summarizes the most recent studies assessing the role of redox homeostasis, autophagy, and chemoresistance in CSCs, including some novel findings on microRNAs and their role in horizontal transfer within cancer cell populations. Future Directions: Rational anticancer therapy and prevention should rely on the fact that cancer is a redox disease with the CSCs being the apex modulated by redox-mediated autophagy. Antioxid. Redox Signal. 28, 1066-1079.
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Affiliation(s)
- Matilde E Lleonart
- Biomedical Research in Cancer Stem Cells, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Etna Abad
- Biomedical Research in Cancer Stem Cells, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Dmitry Graifer
- Faculty of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
| | - Alex Lyakhovich
- Biomedical Research in Cancer Stem Cells, Vall d'Hebron Research Institute, Barcelona, Spain.,Institute of Molecular Biology and Biophysics, Novosibirsk, Russia.,ICRC-FNUSA, International Clinical Research Center and St. Anne's University Hospital Brno, Brno, Czech Republic
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47
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Raju GSR, Pavitra E, Merchant N, Lee H, Prasad GLV, Nagaraju GP, Huh YS, Han YK. Targeting autophagy in gastrointestinal malignancy by using nanomaterials as drug delivery systems. Cancer Lett 2018; 419:222-232. [DOI: 10.1016/j.canlet.2018.01.044] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/12/2018] [Accepted: 01/12/2018] [Indexed: 02/06/2023]
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48
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Marie-Egyptienne DT, Chaudary N, Kalliomäki T, Hedley DW, Hill RP. Cancer initiating-cells are enriched in the CA9 positive fraction of primary cervix cancer xenografts. Oncotarget 2018; 8:1392-1404. [PMID: 27901496 PMCID: PMC5352063 DOI: 10.18632/oncotarget.13625] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 11/07/2016] [Indexed: 12/27/2022] Open
Abstract
Numerous studies have suggested that Cancer Initiating Cells (CIC) can be identified/enriched in cell populations obtained from solid tumors based on the expression of cell surface marker proteins. We used early passage primary cervix cancer xenografts to sort cells based on the expression of the intrinsic hypoxia marker Carbonic Anhydrase 9 (CA9) and tested their cancer initiation potential by limiting dilution assay. We demonstrated that CICs are significantly enriched in the CA9+ fraction in 5/6 models studied. Analyses of the expression of the stem cell markers Oct4, Notch1, Sca-1 & Bmi1 showed a trend toward an increase in the CA9+ populations, albeit not significant. We present evidence that enhanced autophagy does not play a role in the enhanced growth of the CA9+ cells. Our study suggests a direct in vivo functional link between hypoxic cells and CICs in primary cervix cancer xenografts.
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Affiliation(s)
- Delphine Tamara Marie-Egyptienne
- Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network and Campbell Family Institute for Cancer Research, Toronto, Ontario, M5G2M9, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Naz Chaudary
- Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network and Campbell Family Institute for Cancer Research, Toronto, Ontario, M5G2M9, Canada
| | - Tuula Kalliomäki
- Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network and Campbell Family Institute for Cancer Research, Toronto, Ontario, M5G2M9, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - David William Hedley
- Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network and Campbell Family Institute for Cancer Research, Toronto, Ontario, M5G2M9, Canada.,Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, M5G2M9, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada
| | - Richard Peter Hill
- Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network and Campbell Family Institute for Cancer Research, Toronto, Ontario, M5G2M9, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
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49
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Bauer AS, Nazarov PV, Giese NA, Beghelli S, Heller A, Greenhalf W, Costello E, Muller A, Bier M, Strobel O, Hackert T, Vallar L, Scarpa A, Büchler MW, Neoptolemos JP, Kreis S, Hoheisel JD. Transcriptional variations in the wider peritumoral tissue environment of pancreatic cancer. Int J Cancer 2018; 142:1010-1021. [PMID: 28983920 PMCID: PMC5813190 DOI: 10.1002/ijc.31087] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 08/10/2017] [Accepted: 08/30/2017] [Indexed: 01/23/2023]
Abstract
Transcriptional profiling was performed on 452 RNA preparations isolated from various types of pancreatic tissue from tumour patients and healthy donors, with a particular focus on peritumoral samples. Pancreatic ductal adenocarcinomas (PDAC) and cystic tumours were most different in these non-tumorous tissues surrounding them, whereas the actual tumours exhibited rather similar transcript patterns. The environment of cystic tumours was transcriptionally nearly identical to normal pancreas tissue. In contrast, the tissue around PDAC behaved a lot like the tumour, indicating some kind of field defect, while showing far less molecular resemblance to both chronic pancreatitis and healthy tissue. This suggests that the major pathogenic difference between cystic and ductal tumours may be due to their cellular environment rather than the few variations between the tumours. Lack of correlation between DNA methylation and transcript levels makes it unlikely that the observed field defect in the peritumoral tissue of PDAC is controlled to a large extent by such epigenetic regulation. Functionally, a strikingly large number of autophagy-related transcripts was changed in both PDAC and its peritumoral tissue, but not in other pancreatic tumours. A transcription signature of 15 autophagy-related genes was established that permits a prognosis of survival with high accuracy and indicates the role of autophagy in tumour biology.
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Affiliation(s)
- Andrea S. Bauer
- Division of Functional Genome AnalysisGerman Cancer Research Centre (DKFZ)HeidelbergGermany
| | - Petr V. Nazarov
- Genomics and Proteomics Research Unit, Luxembourg Institute of HealthLuxembourg CityLuxembourg
| | - Nathalia A. Giese
- Department of General SurgeryUniversity Hospital HeidelbergHeidelbergGermany
| | - Stefania Beghelli
- Department of Pathology and DiagnosticsUniversità di VeronaVeronaItaly
| | - Anette Heller
- Department of General SurgeryUniversity Hospital HeidelbergHeidelbergGermany
| | - William Greenhalf
- National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine CentreLiverpoolUnited Kingdom
| | - Eithne Costello
- National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine CentreLiverpoolUnited Kingdom
| | - Arnaud Muller
- Genomics and Proteomics Research Unit, Luxembourg Institute of HealthLuxembourg CityLuxembourg
| | - Melanie Bier
- Division of Functional Genome AnalysisGerman Cancer Research Centre (DKFZ)HeidelbergGermany
| | - Oliver Strobel
- Department of General SurgeryUniversity Hospital HeidelbergHeidelbergGermany
| | - Thilo Hackert
- Department of General SurgeryUniversity Hospital HeidelbergHeidelbergGermany
| | - Laurent Vallar
- Genomics and Proteomics Research Unit, Luxembourg Institute of HealthLuxembourg CityLuxembourg
| | - Aldo Scarpa
- Department of Pathology and DiagnosticsUniversità di VeronaVeronaItaly
| | - Markus W. Büchler
- Department of General SurgeryUniversity Hospital HeidelbergHeidelbergGermany
| | - John P. Neoptolemos
- National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine CentreLiverpoolUnited Kingdom
| | - Stephanie Kreis
- Life Sciences Research Unit, University of LuxembourgLuxembourg CityLuxembourg
| | - Jörg D. Hoheisel
- Division of Functional Genome AnalysisGerman Cancer Research Centre (DKFZ)HeidelbergGermany
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50
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Phi LTH, Sari IN, Yang YG, Lee SH, Jun N, Kim KS, Lee YK, Kwon HY. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells Int 2018; 2018:5416923. [PMID: 29681949 PMCID: PMC5850899 DOI: 10.1155/2018/5416923] [Citation(s) in RCA: 612] [Impact Index Per Article: 87.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 01/11/2018] [Indexed: 12/14/2022] Open
Abstract
Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are suggested to be responsible for drug resistance and cancer relapse due in part to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells. Thus, it is important to understand the characteristics and mechanisms by which CSCs display resistance to therapeutic agents. In this review, we highlight the key features and mechanisms that regulate CSC function in drug resistance as well as recent breakthroughs of therapeutic approaches for targeting CSCs. This promises new insights of CSCs in drug resistance and provides better therapeutic rationales to accompany novel anticancer therapeutics.
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Affiliation(s)
- Lan Thi Hanh Phi
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Ita Novita Sari
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Ying-Gui Yang
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Sang-Hyun Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Nayoung Jun
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Kwang Seock Kim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Yun Kyung Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Hyog Young Kwon
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
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