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Castagnoli L, Franceschini A, Cancila V, Dugo M, Bigliardi M, Chiodoni C, Toneguzzo P, Regondi V, Corsetto PA, Pietrantonio F, Mazzucchelli S, Corsi F, Belfiore A, Vingiani A, Pruneri G, Ligorio F, Colombo MP, Tagliabue E, Tripodo C, Vernieri C, Triulzi T, Pupa SM. CD36 enrichment in HER2-positive mesenchymal stem cells drives therapy refractoriness in breast cancer. J Exp Clin Cancer Res 2025; 44:19. [PMID: 39833955 PMCID: PMC11744895 DOI: 10.1186/s13046-025-03276-z] [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: 03/27/2024] [Accepted: 01/03/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Growing evidence shows that the reprogramming of fatty acid (FA) metabolism plays a key role in HER2-positive (HER2 +) breast cancer (BC) aggressiveness, therapy resistance and cancer stemness. In particular, HER2 + BC has been defined as a "lipogenic disease" due to the functional and bi-directional crosstalk occurring between HER2-mediated oncogenic signaling and FA biosynthesis via FA synthase activity. In this context, the functional role exerted by the reprogramming of CD36-mediated FA uptake in HER2 + BC poor prognosis and therapy resistance remains unclear. In this study, we aimed to elucidate whether enhanced CD36 in mesenchymal HER2 + cancer stem cells (CSCs) is directly involved in anti-HER2 treatment refractoriness in HER2 + BC and to design future metabolism-based approaches targeting both FA reprogramming and the "root" of cancer. METHODS Molecular, biological and functional characterization of CD36-mediated FA uptake was investigated in HER2 + BC patients, cell lines, epithelial and mesenchymal CSCs. Cell proliferation was analyzed by SRB assay upon treatment with lapatinib, CD36 inhibitor, or Wnt antagonist/agonist. Engineered cell models were generated via lentivirus infection and transient silencing. CSC-like properties and tumorigenesis of HER2 + BC cells with or without CD36 depletion were examined by mammosphere forming efficiency assay, flow cytometry, cell sorting, ALDH activity assay and xenograft mouse model. FA uptake was examined by flow cytometry with FA BODIPY FL C16. Intratumor expression of CSC subsets was evaluated via multiplex immunostaining and immunolocalization analysis. RESULTS Molecular data demonstrated that CD36 is significantly upmodulated on treatment in therapy resistant HER2 + BC patients and its expression levels in BC cells is correlated with FA uptake. We provided evidence of a consistent enrichment of CD36 in HER2 + epithelial-mesenchymal transition (EMT)-like CSCs from all tested resistant cell models that mechanistically occurs via Wnt signaling pathway activation. Consistently, both in vitro and in vivo dual blockade of CD36 and HER2 increased the anti-CSC efficacy of anti-HER2 drugs favoring the transition of the therapy resistant mesenchymal CSCs into therapy-sensitive mesenchymal-epithelial transition (MET)-like epithelial state. In addition, expression of CD36 in intratumor HER2 + mesenchymal CSCs is significantly associated with resistance to trastuzumab in HER2 + BC patients. CONCLUSIONS These results support the metabolo-oncogenic nature of CD36-mediated FA uptake in HER2 + therapy-refractory BC. Our study provides evidence that targeting CD36 might be an effective metabolic therapeutic strategy in the treatment of this malignancy.
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Affiliation(s)
- Lorenzo Castagnoli
- Microenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Amadeolab Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
| | - Alma Franceschini
- Microenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Amadeolab Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
| | - Valeria Cancila
- Tumor Immunology Unit, Department PROMISE, Universita' Di Palermo, Palermo, Italy
| | - Matteo Dugo
- Breast Cancer Unit Clinical Translational and Immunotherapy Research, Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Martina Bigliardi
- Microenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Amadeolab Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
| | - Claudia Chiodoni
- Molecular Immunology Unit, Department of Experimental Oncology, Amadeolab Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
| | - Paolo Toneguzzo
- Microenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Amadeolab Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
| | - Viola Regondi
- Microenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Amadeolab Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
| | - Paola A Corsetto
- Department of Pharmacologicaland, Biomolecular Sciences "Rodolfo Paoletti", Università Di Milano, Milan, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
| | - Serena Mazzucchelli
- Department of Biomedical and Clinical Sciences, Università Di Milano, Milan, Italy
| | - Fabio Corsi
- Surgery Department, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Antonio Belfiore
- Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
| | - Antonio Vingiani
- Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
- Department of Oncology and Hemato-Oncology, Universita' di Milano, Milan, Italy
| | - Giancarlo Pruneri
- Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
- Department of Oncology and Hemato-Oncology, Universita' di Milano, Milan, Italy
| | - Francesca Ligorio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
- IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy
| | - Mario P Colombo
- Molecular Immunology Unit, Department of Experimental Oncology, Amadeolab Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
| | - Elda Tagliabue
- Microenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Amadeolab Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
| | - Claudio Tripodo
- Tumor Immunology Unit, Department PROMISE, Universita' Di Palermo, Palermo, Italy
- IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy
| | - Claudio Vernieri
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
- IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy
| | - Tiziana Triulzi
- Microenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Amadeolab Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy
| | - Serenella M Pupa
- Microenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Amadeolab Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Milan, Italy.
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Hosseini A, Eghtedari AR, Mirzaei A, Babaheidarian P, Nekoufar S, Khademian N, Jamshidi K, Tavakoli-Yaraki M. The clinical significance of CD44v6 in malignant and benign primary bone tumors. BMC Musculoskelet Disord 2023; 24:607. [PMID: 37491225 PMCID: PMC10367246 DOI: 10.1186/s12891-023-06738-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 07/19/2023] [Indexed: 07/27/2023] Open
Abstract
BACKGROUND The objective of this study was to assess the expression profile of CD44v6, a potential cancer stem cell marker, and its diagnostic and predictive significance in three distinct types of primary bone tumors. METHODS In this study, we utilized real-time qRT-PCR and immunohistochemistry to examine the gene and protein levels of CD44v6 in a total of 138 fresh bone tissues. This included 69 tumor tissues comprising osteosarcoma (N = 23), chondrosarcoma (N = 23), and GCT (N = 23), as well as 69 corresponding non-cancerous tumor margins. Furthermore, we investigated the circulating level of CD44v6 by isolating peripheral blood mononuclear cells from 92 blood samples. Among these, 69 samples were obtained from patients diagnosed with primary bone tumors, while the remaining 23 samples were from healthy donors. The primary objectives of our investigation were to assess the correlation between CD44v6 expression levels and clinic-pathological features of the patients, as well as to evaluate the diagnostic and predictive values of CD44v6 in this context. RESULTS In patients with osteosarcoma and chondrosarcoma tumors, both the gene and protein expression of CD44v6 were found to be significantly higher compared to the GCT group. Furthermore, the circulating level of CD44v6 was notably elevated in patients diagnosed with osteosarcoma and chondrosarcoma in comparison to the GCT group and patients with malignant tumor characteristics. Additionally, we observed a strong correlation between the gene and protein levels of CD44v6 and important tumor indicators such as tumor grade, metastasis, recurrence, and size at the tumor site. CD44v6 shows potential in differentiating patients with bone tumors from both control groups and tumor groups with severe and invasive characteristics from those with non-severe features. Importantly, the expression level of CD44v6 also demonstrated predictive value for determining tumor grade and the likelihood of recurrence. CONCLUSION CD44v6 is likely to play a role in the development of primary bone tumors and has the potential to serve as a diagnostic biomarker for bone cancer. However, to obtain more accurate and conclusive findings, further mechanistic investigations involving larger population samples are necessary.
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Affiliation(s)
- Ameinh Hosseini
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran
| | - Amir Reza Eghtedari
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran
| | - Alireza Mirzaei
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Pegah Babaheidarian
- Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Nekoufar
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran
| | - Narges Khademian
- Department of Clinical Biochemistry, School of Medicine, Tarbiat Modares University, Tehran, Iran
| | - Khodamorad Jamshidi
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Tavakoli-Yaraki
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran.
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Ambrose JM, Veeraraghavan VP, Vennila R, Rupert S, Sathyanesan J, Meenakshisundaram R, Selvaraj S, Malayaperumal S, Kullappan M, Dorairaj S, Gujarathi JR, Gandhamaneni SH, Surapaneni KM. Comparison of mammosphere formation from stem-like cells of normal breast, malignant primary breast tumors, and MCF-7 cell line. J Egypt Natl Canc Inst 2022; 34:51. [PMID: 36504339 DOI: 10.1186/s43046-022-00152-1] [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: 11/04/2021] [Accepted: 09/14/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Mammosphere formation assay has become a versatile tool to quantify the activity of putative breast cancer stem cells in non-adherent in vitro cultures. However, optimizing the suspension culture system is crucial to establish mammosphere cultures from primary breast tumors. METHODS This study aimed at determining the self-renewal and sphere-forming potential of breast cancer stem-like cells derived from human primary invasive ductal carcinoma and normal breast tissue samples, and MCF-7 breast cancer cell line using an optimal suspension culture system. Mammosphere-forming efficiency of the mammospheres generated from the tissue samples and cell line were compared. We evaluated the expression of CD44+/CD24-/low and CD49f+/EpCAM-/low phenotypes in the stem-like cells by flow cytometry. CK-18, CK-19, α-SMA, and EpCAM marker expression was assessed using immunohistochemical staining. RESULTS Breast epithelial cells isolated from the three samples formed two-dimensional spheroids in suspension cultures. Interestingly, mammospheres formed from patient-derived primary breast tumors were enriched in breast cancer stem-like cells with the phenotype CD44+/CD24-/low and exhibited a relatively more number of large spheres when compared to the normal breast stem cells. MCF-7-derived SCs were more aggressive and resulted in the formation of a significantly higher number of spheroids. The expression of CK-18/CK-19 and α-SMA/EpCAM proteins was confirmed in breast cancer tissues. CONCLUSIONS Thus, the use of primary tumor specimens and breast cancer cell lines as suitable models for elucidating the breast cancer stem cell activity was validated using mammosphere culture system.
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Affiliation(s)
- Jenifer Mallavarpu Ambrose
- Department of Research, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Poonamallee, Chennai, Tamil Nadu, 600 123, India
| | - Vishnu Priya Veeraraghavan
- Department of Biochemistry, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Velappanchavadi, Chennai, Tamil Nadu, 600 077, India
| | - Rosy Vennila
- Stem Cell Research Centre, Government Stanley Medical College & Hospital, Chennai, Tamil Nadu, 600 001, India
| | - Secunda Rupert
- Stem Cell Research Centre, Government Stanley Medical College & Hospital, Chennai, Tamil Nadu, 600 001, India
| | - Jeswanth Sathyanesan
- Stem Cell Research Centre, Government Stanley Medical College & Hospital, Chennai, Tamil Nadu, 600 001, India
| | | | - Sakthivel Selvaraj
- Stem Cell Research Centre, Government Stanley Medical College & Hospital, Chennai, Tamil Nadu, 600 001, India
| | - Sarubala Malayaperumal
- Stem Cell Research Centre, Government Stanley Medical College & Hospital, Chennai, Tamil Nadu, 600 001, India
| | - Malathi Kullappan
- Department of Research, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Poonamallee, Chennai, Tamil Nadu, 600 123, India
| | - Sudarsanam Dorairaj
- PG Research Department of Advanced Zoology and Biotechnology, Loyola College, Chennai, Tamil Nadu, 600 034, India
| | - Jayesh R Gujarathi
- Department of Chemistry, School of Chemical Sciences, KES's Pratap College, Amalner, Maharashtra, 425 401, India
| | - Sri Harshini Gandhamaneni
- Department of General Medicine, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Poonamallee, Chennai, Tamil Nadu, 600 123, India
| | - Krishna Mohan Surapaneni
- Departments of Biochemistry, Molecular Virology, Research, Clinical Skills & Simulation, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Poonamallee, Chennai, Tamil Nadu, 600 123, India.
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Khan S, Suryavanshi M, Kaur J, Nayak D, Khurana A, Manchanda RK, Tandon C, Tandon S. Stem cell therapy: A paradigm shift in breast cancer treatment. World J Stem Cells 2021; 13:841-860. [PMID: 34367480 PMCID: PMC8316873 DOI: 10.4252/wjsc.v13.i7.841] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/30/2021] [Accepted: 06/17/2021] [Indexed: 02/07/2023] Open
Abstract
As per the latest Globocan statistics, the high prevalence rate of breast cancer in low- and middle-income countries has led to it becoming the most common cancer to be diagnosed, hence posing a major public health challenge. As per this data, more than 11.7% of the estimated new cancer cases in 2020 were due to breast cancer. A small but significant subpopulation of cells with self- renewing ability are present in the tumor stroma and have been given the nomenclature of cancer stem cells (CSCs). These cells display a high degree of plasticity owing to their ability to transition from the slowly cycling quiescent phase to the actively proliferating phenotype. This attribute of CSCs allows them to differentiate into various cell types having diverse functions. Breast CSCs have a pivotal role in development, metastasis, treatment resistance and relapse of breast cancers. This review focuses on the pathways regulating breast CSC maintenance and the current strategies that are being explored for directing the development of novel, targeted, therapeutic approaches for limiting and eradicating this aberrant stem cell population.
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Affiliation(s)
- Sabiha Khan
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India
| | - Moushumi Suryavanshi
- Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi 110085, India
| | - Jasamrit Kaur
- Department of Chemistry, Goswami Ganesh Dutta Sanatan Dharma College, Chandigarh 160030, India
| | - Debadatta Nayak
- Central Council for Research in Homeopathy, New Delhi 110058, India
| | - Anil Khurana
- Central Council for Research in Homeopathy, New Delhi 110058, India
| | | | - Chanderdeep Tandon
- Amity Institute of Biotechnology, Amity University, Noida 201313, Uttar Pradesh, India
| | - Simran Tandon
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India
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Peng X, Wei Z, Gerweck LE. Making radiation therapy more effective in the era of precision medicine. PRECISION CLINICAL MEDICINE 2020; 3:272-283. [PMID: 35692625 PMCID: PMC8982539 DOI: 10.1093/pcmedi/pbaa038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 11/18/2020] [Accepted: 11/22/2020] [Indexed: 02/05/2023] Open
Abstract
Cancer has become a leading cause of death and constitutes an enormous burden worldwide. Radiation is a principle treatment modality used alone or in combination with other forms of therapy, with 50%–70% of cancer patients receiving radiotherapy at some point during their illness. It has been suggested that traditional radiotherapy (daily fractions of approximately 1.8–2 Gy over several weeks) might select for radioresistant tumor cell sub-populations, which, if not sterilized, give rise to local treatment failure and distant metastases. Thus, the challenge is to develop treatment strategies and schedules to eradicate the resistant subpopulation of tumorigenic cells rather than the predominant sensitive tumor cell population. With continued technological advances including enhanced conformal treatment technology, radiation oncologists can increasingly maximize the dose to tumors while sparing adjacent normal tissues, to limit toxicity and damage to the latter. Increased dose conformality also facilitates changes in treatment schedules, such as changes in dose per treatment fraction and number of treatment fractions, to enhance the therapeutic ratio. For example, the recently developed large dose per fraction treatment schedules (hypofractionation) have shown clinical advantage over conventional treatment schedules in some tumor types. Experimental studies suggest that following large acute doses of radiation, recurrent tumors, presumably sustained by the most resistant tumor cell populations, may in fact be equally or more radiation sensitive than the primary tumor. In this review, we summarize the related advances in radiotherapy, including the increasing understanding of the molecular mechanisms of radioresistance, and the targeting of these mechanisms with potent small molecule inhibitors, which may selectively sensitize tumor cells to radiation.
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Affiliation(s)
- Xingchen Peng
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Zhigong Wei
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Leo E Gerweck
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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Pesarrodona M, Sánchez-García L, Seras-Franzoso J, Sánchez-Chardi A, Baltá-Foix R, Cámara-Sánchez P, Gener P, Jara JJ, Pulido D, Serna N, Schwartz S, Royo M, Villaverde A, Abasolo I, Vazquez E. Engineering a Nanostructured Nucleolin-Binding Peptide for Intracellular Drug Delivery in Triple-Negative Breast Cancer Stem Cells. ACS APPLIED MATERIALS & INTERFACES 2020; 12:5381-5388. [PMID: 31840972 DOI: 10.1021/acsami.9b15803] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Five peptide ligands of four different cell surface receptors (nucleolin, CXCR1, CMKLR1, and CD44v6) have been evaluated as targeting moieties for triple-negative human breast cancers. Among them, the peptide F3, derived from phage display, promotes the fast and efficient internalization of a genetically fused green fluorescent protein (GFP) inside MDA-MB-231 cancer stem cells in a specific receptor-dependent fashion. The further engineering of this protein into the modular construct F3-RK-GFP-H6 and the subsequent construct F3-RK-PE24-H6 resulted in self-assembling polypeptides that organize as discrete and regular nanoparticles. These materials, 15-20 nm in size, show enhanced nucleolin-dependent cell penetrability. We show that the F3-RK-PE24-H6, based on the Pseudomonas aeruginosa exotoxin A (PE24) as a core functional domain, is highly cytotoxic over target cells. The combination of F3, the cationic peptide (RK)n, and the toxin domain PE24 in such unusual presentation appears as a promising approach to cell-targeted drug carriers in breast cancers and addresses selective drug delivery in otherwise difficult-to-treat triple-negative breast cancers.
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Affiliation(s)
- Mireia Pesarrodona
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
| | - Laura Sánchez-García
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
| | | | | | | | - Patricia Cámara-Sánchez
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
| | - Petra Gener
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
| | - José Juan Jara
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
| | - Daniel Pulido
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
- Multivalent Systems for Nanomedicine , Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) , Barcelona , 08034 , Spain
| | - Naroa Serna
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
| | - Simó Schwartz
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
| | - Miriam Royo
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
- Multivalent Systems for Nanomedicine , Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) , Barcelona , 08034 , Spain
| | - Antonio Villaverde
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
| | - Ibane Abasolo
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
| | - Esther Vazquez
- CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain
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Hara T, Makino T, Yamasaki M, Tanaka K, Miyazaki Y, Takahashi T, Kurokawa Y, Nakajima K, Matsuura N, Mori M, Doki Y. Effect of c-Met and CD44v6 Expression in Resistance to Chemotherapy in Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 2019; 26:899-906. [PMID: 30610559 DOI: 10.1245/s10434-018-07126-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND c-Met relies on CD44v6 for its activation and signaling in several cancer cell lines. However, the correlation of c-Met and CD44v6 expression and its biological significance in esophageal squamous cell carcinoma (ESCC) remains unknown. METHODS Expression of c-Met and CD44v6 was examined by immunohistochemistry (IHC) in 147 ESCC specimens. We analyzed the impact of c-Met and CD44v6 expression on clinicopathological parameters, including chemoresistance or prognosis in ESCC. RESULTS High expression of c-Met and CD44v6 in cancerous lesions was identified in 49.7% and 50.3% of all patients, respectively. The c-Met-high group comprised more advanced pT and pM stages than the c-Met-low group. In addition, more patients in the c-Met-high group received neoadjuvant chemotherapy (NACT) than the c-Met-low group (64.4% vs. 43.2%, P = 0.010). On the other hand, the CD44v6-high group was associated with more advanced pT/pN stages and a poorer clinical response to NACT (response rate 53.5% vs. 77.8%, P = 0.025) than the CD44v6-low group. Double-positive immunostaining of c-Met and CD44v6 was identified in 28.6% of all cases, and multivariate analysis of overall survival (OS) identified them (hazard ratio 1.79, 95% confidence interval 1.03-3.04, P = 0.038) as independent prognostic factors in addition to pN and pM stage. CONCLUSIONS c-Met/CD44v6 were associated with tumor progression or chemoresistance. Double-positive expression of c-Met and CD44v6 negatively impacted patient prognosis in ESCC, implying that c-Met and CD44v6 are candidates for targeted therapy in ESCC.
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Affiliation(s)
- Takeo Hara
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan.
| | - Makoto Yamasaki
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan
| | - Koji Tanaka
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan
| | - Yasuhiro Miyazaki
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan
| | - Nariaki Matsuura
- Osaka International Cancer Institute, Osaka, Osaka, Japan.,Department of Molecular Pathology, Osaka University Graduate School of Medicine, Division of Health Sciences, Suita City, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan
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Avitabile E, Bedognetti D, Ciofani G, Bianco A, Delogu LG. How can nanotechnology help the fight against breast cancer? NANOSCALE 2018; 10:11719-11731. [PMID: 29917035 DOI: 10.1039/c8nr02796j] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
In this review we provide a broad overview on the use of nanotechnology for the fight against breast cancer (BC). Nowadays, detection, diagnosis, treatment, and prevention may be possible thanks to the application of nanotechnology to clinical practice. Taking into consideration the different forms of BC and the disease status, nanomaterials can be designed to meet the most forefront objectives of modern therapy and diagnosis. We have analyzed in detail three main groups of nanomaterial applications for BC treatment and diagnosis. We have identified several types of drugs successfully conjugated with nanomaterials. We have analyzed the main important imaging techniques and all nanomaterials used to help the non-invasive, early detection of the lesions. Moreover, we have examined theranostic nanomaterials as unique tools, combining imaging, detection, and therapy for BC. This state of the art review provides a useful guide depicting how nanotechnology can be used to overcome the current barriers in BC clinical practice, and how it will shape the future scenario of treatments, prevention, and diagnosis, revolutionizing the current approaches, e.g., reducing the suffering related to chemotherapy.
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Affiliation(s)
- Elisabetta Avitabile
- Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100 Sassari, Italy.
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9
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In vivo tracking of adipose tissue grafts with cadmium-telluride quantum dots. Arch Plast Surg 2018; 45:111-117. [PMID: 29506330 PMCID: PMC5869436 DOI: 10.5999/aps.2017.01487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 12/09/2017] [Accepted: 12/27/2017] [Indexed: 11/23/2022] Open
Abstract
Background Fat grafting, or lipofilling, represent frequent clinically used entities. The fate of these transplants is still not predictable, whereas only few animal models are available for further research. Quantum dots (QDs) are semiconductor nanocrystals which can be conveniently tracked in vivo due to photoluminescence. Methods Fat grafts in cluster form were labeled with cadmium-telluride (CdTe)-QD 770 and transplanted subcutaneously in a murine in vivo model. Photoluminescence levels were serially followed in vivo. Results Tracing of fat grafts was possible for 50 days with CdTe-QD 770. The remaining photoluminescence was 4.9%±2.5% for the QDs marked fat grafts after 30 days and 4.2%± 1.7% after 50 days. There was no significant correlation in the relative course of the tracking signal, when vital fat transplants were compared to non-vital graft controls. Conclusions For the first-time fat grafts were tracked in vivo with CdTe-QDs. CdTe-QDs could offer a new option for in vivo tracking of fat grafts for at least 50 days, but do not document vitality of the grafts.
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10
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Strietz J, Stepputtis SS, Preca BT, Vannier C, Kim MM, Castro DJ, Au Q, Boerries M, Busch H, Aza-Blanc P, Heynen-Genel S, Bronsert P, Kuster B, Stickeler E, Brabletz T, Oshima RG, Maurer J. ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer. Oncotarget 2018; 7:83278-83293. [PMID: 27829216 PMCID: PMC5347769 DOI: 10.18632/oncotarget.13086] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 10/21/2016] [Indexed: 12/21/2022] Open
Abstract
Cancers are heterogeneous by nature. While traditional oncology screens commonly use a single endpoint of cell viability, altering the phenotype of tumor-initiating cells may reveal alternative targets that regulate cellular growth by processes other than apoptosis or cell division. We evaluated the impact of knocking down expression of 420 kinases in bi-lineage triple-negative breast cancer (TNBC) cells that express characteristics of both myoepithelial and luminal cells. Knockdown of ERN1 or ALPK1 induces bi-lineage MDA-MB-468 cells to lose the myoepithelial marker keratin 5 but not the luminal markers keratin 8 and GATA3. In addition, these cells exhibit increased β-casein production. These changes are associated with decreased proliferation and clonogenicity in spheroid cultures and anchorage-independent growth assays. Confirmation of these assays was completed in vivo, where ERN1- or ALPK1-deficient TNBC cells are less tumorigenic. Finally, treatment with K252a, a kinase inhibitor active on ERN1, similarly impairs anchorage-independent growth of multiple breast cancer cell lines. This study supports the strategy to identify new molecular targets for types of cancer driven by cells that retain some capacity for normal differentiation to a non-tumorigenic phenotype. ERN1 and ALPK1 are potential targets for therapeutic development.
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Affiliation(s)
- Juliane Strietz
- Department of Visceral Surgery, University Hospital Freiburg, German Cancer Consortium (DKTK), Freiburg, Germany
| | - Stella S Stepputtis
- Department of Visceral Surgery, University Hospital Freiburg, German Cancer Consortium (DKTK), Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Bogdan-Tiberius Preca
- Department of Visceral Surgery, University Hospital Freiburg, German Cancer Consortium (DKTK), Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Corinne Vannier
- Department of Visceral Surgery, University Hospital Freiburg, German Cancer Consortium (DKTK), Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mihee M Kim
- Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany
| | - David J Castro
- Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany
| | - Qingyan Au
- Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany
| | - Melanie Boerries
- German Cancer Research Center (DKFZ), Heidelberg, Germany.,Systems Biology of the Cellular Microenvironment at The DKFZ Partner Site Freiburg, German Cancer Consortium (DKTK), Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Hauke Busch
- German Cancer Research Center (DKFZ), Heidelberg, Germany.,Systems Biology of the Cellular Microenvironment at The DKFZ Partner Site Freiburg, German Cancer Consortium (DKTK), Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Pedro Aza-Blanc
- Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany
| | | | - Peter Bronsert
- Department of Surgical Pathology, University Medical Center Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany
| | - Bernhard Kuster
- Technische Universitaet Muenchen, Partner Site of the German Cancer Consortium, Freising, Germany
| | - Elmar Stickeler
- Department of OBGYN, University Clinic Aachen (UKA), Aachen, Germany
| | - Thomas Brabletz
- Department of Experimental Medicine I, University of Erlangen-Nuernberg, Erlangen, Germany
| | - Robert G Oshima
- Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany
| | - Jochen Maurer
- Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany
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Abstract
Cancer stem cells have genetic and functional characteristics that can turn them resistant to standard cancer therapeutic targets. Identification of these cells is challenging and is mostly done by detecting the expression of their antigens in a group of stem cells. Currently, there are a significant number of surface markers available which can detect the cancer stem cells by directly targeting their specific antigens present in cells. These markers possess differential expression patterns and sub-localizations in cancer stem cells when compared to non-neoplastic stem cells and somatic cells. In addition to molecular markers, multiple analytical methods and techniques including functional assays, cell sorting, filtration approaches, and xenotransplantation methods are used to identify cancer stem cells. This chapter will overview the functional significance of cancer stem cells, its biological correlations, specific markers, and detection methods.
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Affiliation(s)
- Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast Campus, Gold Coast, QLD, 4222, Australia
| | - Farhadul Islam
- Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast Campus, Gold Coast, QLD, 4222, Australia
| | - Alfred King-Yin Lam
- Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast Campus, Gold Coast, QLD, 4222, Australia.
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12
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P-cadherin: a useful biomarker for axillary-based breast cancer decisions in the clinical practice. Mod Pathol 2017; 30:698-709. [PMID: 28084338 DOI: 10.1038/modpathol.2016.232] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 11/29/2016] [Accepted: 11/29/2016] [Indexed: 02/06/2023]
Abstract
Axillary lymph node metastases represent the most powerful breast cancer prognostic factor, dictating disease staging and clinical therapeutic decisions. Nonetheless, breast cancer patients with positive lymph nodes still exhibit a heterogeneous behavior regarding disease progression. Stem-like subpopulations of cancer cells show high migratory and metastatic capacity, thus we hypothesize that breast cancer stem cell markers evaluation in metastasized lymph nodes could provide a more accurate prediction of patient's prognosis. Therefore, the expression profile of P-cadherin, CD44, and CD49f, which have been already associated to stem cell properties in breast cancer, has been evaluated by immunohistochemistry in a series of 135 primary tumors and matched axillary lymph node metastases from 135 breast cancer patients. Taking in consideration the expression of the stem cell markers only in axillary nodes, P-cadherin was the only biomarker significantly associated with poor disease-free and overall patient's survival. Moreover, although a concordant expression between primary tumors and matched lymph nodes has been found in the majority of the cases, a small but significant percentage displayed divergent expression (18.2-26.2%). Remarkably, although CD44 and CD49f changes between primary tumors and lymph node metastasis did not impact survival, the cases that were positive for P-cadherin in lymph node metastases being negative in the primary tumor, presented the worst disease-free and overall survival of the whole series. Accordingly, negative cases for this marker in the lymph nodes with positive expression in the matched breast carcinoma demonstrated a better prognosis, which overlapped with tumors that were negative in both sites. P-cadherin and CD49f gain of expression was mainly found in triple-negative carcinomas. Our results indicate for the first time that the evaluation of P-cadherin expression in lymph node metastases is an important predictor of disease outcome, being a putative valuable marker for axillary-based breast cancer decisions in the clinical practice.
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13
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Tudoran OM, Balacescu O, Berindan-Neagoe I. Breast cancer stem-like cells: clinical implications and therapeutic strategies. ACTA ACUST UNITED AC 2016; 89:193-8. [PMID: 27152067 PMCID: PMC4849374 DOI: 10.15386/cjmed-559] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 09/18/2015] [Accepted: 09/22/2015] [Indexed: 12/13/2022]
Abstract
Breast cancer is the most frequently diagnosed cancer in women, being also the leading cause of cancer death among female population, including in Romania. Resistance to therapy represents a major problem for cancer treatment. Current cancer treatments are both expensive and induce serious side effects; therefore ineffective therapies are both traumatic and pricy. Characterizing predictive markers that can identify high-risk patients could contribute to dedicated/personalized therapy to improve the life quality and expectancy of cancer patients. Moreover, there are some markers that govern specific tumor molecular features that can be targeted with specific therapies for those patients who are most likely to benefit. The identification of stem cells in both normal and malignant breast tissue have lead to the hypothesis that breast tumors arise from breast cancer stem-like cells (CSCs), and that these cells influence tumor’s response to therapy. CSCs have similar self-renewal properties to normal stem cells, however the balance between the signaling pathways is altered towards tumor formation In this review, we discuss the molecular aspects of breast CSCs and the controversies regarding their use in the diagnosis and treatment decision of breast cancer patients.
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Affiliation(s)
- Oana Mihaela Tudoran
- Department of Functional Genomics and Experimental Pathology, I. Chiricuta Oncology Institute, Cluj-Napoca, Romania; Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ovidiu Balacescu
- Department of Functional Genomics and Experimental Pathology, I. Chiricuta Oncology Institute, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Department of Functional Genomics and Experimental Pathology, I. Chiricuta Oncology Institute, Cluj-Napoca, Romania; Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Xu C, Sun X, Qin S, Wang H, Zheng Z, Xu S, Luo G, Liu P, Liu J, Du N, Zhang Y, Liu D, Ren H. Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells. Cell Cycle 2016; 14:1686-97. [PMID: 25955298 DOI: 10.1080/15384101.2015.1030547] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Breast cancer stem cells (BCSCs) have the greatest potential to maintain tumorigenesis in all subtypes of tumor cells and were regarded as the key drivers of tumor. Recent evidence has demonstrated that BCSCs contributed to a high degree of resistance to therapy. However, how BCSCs self renewal and tumorigenicity are maintained remains obscure. Herein, our study illustrated that overexpression of let-7a reduced cell proliferation and mammosphere formation ability of breast cancer stem cells(BCSCs) in a KRas-dependent manner through different pathways in vitro and in vivo. To be specific, we provided the evidence that let-7a was decreased, and reversely the expression of KRas was increased with moderate expression in early stages (I/II) and high expression in advanced stages (III/IV) in breast cancer specimens. In addition, the negative correlation between let-7a and KRas was clearly observed. In vitro, we found that let-7a inhibited mammosphere-forming efficiency and the mammosphere-size via NF-κB and MAPK/ERK pathway, respectively. The inhibitory effect of let-7a on mammosphere formation efficiency and the size of mammospheres was abolished after the depletion of KRas. On the contrary, enforced expression of KRas rescued the effect of let-7a. In vivo, let-7a inhibited the growth of tumors, whereas the negative effect of let-7a was rescued after overexpressing KRas. Taken together, our findings suggested that let-7a played a tumor suppressive role in a KRas-dependent manner.
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Affiliation(s)
- Chongwen Xu
- a Second Department of Thoracic Surgery; First Affiliated Hospital; Medical College of Xi'an Jiaotong University ; Xi'an , Shaanxi ; PR China
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15
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Matzke-Ogi A, Jannasch K, Shatirishvili M, Fuchs B, Chiblak S, Morton J, Tawk B, Lindner T, Sansom O, Alves F, Warth A, Schwager C, Mier W, Kleeff J, Ponta H, Abdollahi A, Orian-Rousseau V. Inhibition of Tumor Growth and Metastasis in Pancreatic Cancer Models by Interference With CD44v6 Signaling. Gastroenterology 2016; 150:513-25.e10. [PMID: 26597578 DOI: 10.1053/j.gastro.2015.10.020] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 10/12/2015] [Accepted: 10/13/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Cancer cells with high metastatic potential and stem cell-like characteristics express the cell surface marker CD44. CD44 isoforms that include the v6 exon are co-receptors for the receptor tyrosine kinases MET and Vascular Endothelial Growth factor Receptor-2 (VEGFR-2). We studied CD44v6 signaling in several pancreatic cancer cell lines, and its role in tumor growth and metastasis in several models of pancreatic cancer. METHODS We analyzed the effects of v6 peptides that interfere with the co-receptor functions of CD44v6 for MET and VEGFR-2 in tumors and metastases grown from cells that express different CD44 isoforms, including CD44v6. The peptides were injected into rats with syngeneic tumors and mice with orthotopic or xenograft tumors. We also tested the effects of the peptides in mice with xenograft tumors grown from patient tumor samples and mice that express an oncogenic form of RAS and develop spontaneous pancreatic cancer (KPC mice). We measured levels of CD44v6 messenger RNA (mRNA) in pancreatic cancer tissues from 136 patients. RESULTS Xenograft tumors grown from human cancer cells injected with v6 peptides were smaller and formed fewer metastases in mice. The v6 peptide was more efficient than the MET inhibitor crizotinib and/or the VEGFR-2 inhibitor pazopanib in reducing xenograft tumor growth and metastasis. Injection of KPC mice with the v6 peptide increased their survival time. Injection of mice and rats bearing metastases with the v6 peptide induced regression of metastases. Higher levels of CD44v6 mRNA in human pancreatic tumor tissues were associated with increased expression of MET, tumor metastasis, and shorter patient survival times. CONCLUSIONS Peptide inhibitors of CD44v6 isoforms block tumor growth and metastasis in several independent models of pancreatic cancer. The v6 peptides induced regression of metastases. Levels of CD44v6 mRNA are increased, along with those of MET mRNA, in patients with metastatic pancreatic tumors, compared with nonmetastatic tumors; the increased levels correlated with shorter patient survival time.
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Affiliation(s)
- Alexandra Matzke-Ogi
- Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany; Amcure GmbH, Eggenstein-Leopoldshafen, Germany
| | - Katharina Jannasch
- Department of Hematology and Oncology, University Medicine Göttingen, Göttingen, Germany
| | - Marine Shatirishvili
- Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany
| | - Beatrix Fuchs
- Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany
| | - Sara Chiblak
- Molecular and Translational Radiation Oncology, Heidelberg Institute of Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center, Heidelberg, Germany; The German Cancer Consortium, Heidelberg, Germany
| | - Jennifer Morton
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
| | - Bouchra Tawk
- Molecular and Translational Radiation Oncology, Heidelberg Institute of Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center, Heidelberg, Germany; The German Cancer Consortium, Heidelberg, Germany
| | - Thomas Lindner
- Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany
| | - Owen Sansom
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
| | - Frauke Alves
- Department of Hematology and Oncology, University Medicine Göttingen, Göttingen, Germany
| | - Arne Warth
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Schwager
- Molecular and Translational Radiation Oncology, Heidelberg Institute of Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center, Heidelberg, Germany; The German Cancer Consortium, Heidelberg, Germany
| | - Walter Mier
- Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany
| | - Jörg Kleeff
- Department of Surgery, Technische Universität München, Munich, Germany
| | | | - Amir Abdollahi
- Molecular and Translational Radiation Oncology, Heidelberg Institute of Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center, Heidelberg, Germany; The German Cancer Consortium, Heidelberg, Germany
| | - Véronique Orian-Rousseau
- Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany.
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16
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Stacer AC, Wang H, Fenner J, Dosch JS, Salomonnson A, Luker KE, Luker GD, Rehemtulla A, Ross BD. Imaging Reporters for Proteasome Activity Identify Tumor- and Metastasis-Initiating Cells. Mol Imaging 2015. [DOI: 10.2310/7290.2015.00016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Amanda C. Stacer
- From the Center for Molecular Imaging, Department of Radiology and Departments of Radiation Oncology, Biomedical Engineering, Microbiology and Immunology, and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI
| | - Hanxiao Wang
- From the Center for Molecular Imaging, Department of Radiology and Departments of Radiation Oncology, Biomedical Engineering, Microbiology and Immunology, and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI
| | - Joseph Fenner
- From the Center for Molecular Imaging, Department of Radiology and Departments of Radiation Oncology, Biomedical Engineering, Microbiology and Immunology, and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI
| | - Joseph S. Dosch
- From the Center for Molecular Imaging, Department of Radiology and Departments of Radiation Oncology, Biomedical Engineering, Microbiology and Immunology, and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI
| | - Anna Salomonnson
- From the Center for Molecular Imaging, Department of Radiology and Departments of Radiation Oncology, Biomedical Engineering, Microbiology and Immunology, and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI
| | - Kathryn E. Luker
- From the Center for Molecular Imaging, Department of Radiology and Departments of Radiation Oncology, Biomedical Engineering, Microbiology and Immunology, and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI
| | - Gary D. Luker
- From the Center for Molecular Imaging, Department of Radiology and Departments of Radiation Oncology, Biomedical Engineering, Microbiology and Immunology, and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI
| | - Alnawaz Rehemtulla
- From the Center for Molecular Imaging, Department of Radiology and Departments of Radiation Oncology, Biomedical Engineering, Microbiology and Immunology, and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI
| | - Brian D. Ross
- From the Center for Molecular Imaging, Department of Radiology and Departments of Radiation Oncology, Biomedical Engineering, Microbiology and Immunology, and Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI
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17
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Tudoran O, Soritau O, Balacescu L, Visan S, Barbos O, Cojocneanu-Petric R, Balacescu O, Berindan-Neagoe I. Regulation of stem cells-related signaling pathways in response to doxorubicin treatment in Hs578T triple-negative breast cancer cells. Mol Cell Biochem 2015; 409:163-76. [PMID: 26187676 DOI: 10.1007/s11010-015-2522-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 07/11/2015] [Indexed: 12/30/2022]
Abstract
Different molecular changes have been previously associated with therapeutic response and recurrent disease, however, the detailed mechanism of action in triple-negative breast cancer subtype remains elusive. In this study, we investigated the cellular and molecular signaling of two claudin-low triple-negative breast cancer cells to doxorubicin and docetaxel treatment. Whole human transcriptomic evaluation was used to identify the subsequent changes in gene expression, while biological effects were measured by means of proliferation and anchorage-independent growth assays. Microarray analysis revealed changes in stem cell-related signaling pathways, suggesting that doxorubicin treatment affects the balance between self-renewal and differentiation. While the treatment reduced the proliferation, aggregation and mammosphere forming ability of stem-like cells derived from Hs578T cell line, stem-like cells derived from MDA-MB-231 cells were not significantly affected. Our results suggest that claudin-low triple-negative breast cancer cells might predominantly alter stem cell-related signaling pathways to promote stem-like cells activity as an innate resistance mechanism to doxorubicin treatment.
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Affiliation(s)
- Oana Tudoran
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute I. Chiricuta, Cluj-Napoca, 34-36 Republicii Str, 400015, Cluj-Napoca, Cluj, Romania.
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Gh. Str., 400337, Cluj-Napoca, Romania.
| | - Olga Soritau
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute I. Chiricuta, Cluj-Napoca, 34-36 Republicii Str, 400015, Cluj-Napoca, Cluj, Romania
| | - Loredana Balacescu
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute I. Chiricuta, Cluj-Napoca, 34-36 Republicii Str, 400015, Cluj-Napoca, Cluj, Romania
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Gh. Str., 400337, Cluj-Napoca, Romania
| | - Simona Visan
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute I. Chiricuta, Cluj-Napoca, 34-36 Republicii Str, 400015, Cluj-Napoca, Cluj, Romania
- Department of Pathologic Anatomy, Necropsy and Veterinary Forensic Medicine, University of Agricultural Sciences and Veterinary Medicine, 3-5 Calea Manastur, 400372, Cluj-Napoca, Romania
| | - Otilia Barbos
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute I. Chiricuta, Cluj-Napoca, 34-36 Republicii Str, 400015, Cluj-Napoca, Cluj, Romania
| | - Roxana Cojocneanu-Petric
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Gh. Str., 400337, Cluj-Napoca, Romania
| | - Ovidiu Balacescu
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute I. Chiricuta, Cluj-Napoca, 34-36 Republicii Str, 400015, Cluj-Napoca, Cluj, Romania
| | - Ioana Berindan-Neagoe
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute I. Chiricuta, Cluj-Napoca, 34-36 Republicii Str, 400015, Cluj-Napoca, Cluj, Romania
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Gh. Str., 400337, Cluj-Napoca, Romania
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18
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Jordan AR, Racine RR, Hennig MJP, Lokeshwar VB. The Role of CD44 in Disease Pathophysiology and Targeted Treatment. Front Immunol 2015; 6:182. [PMID: 25954275 PMCID: PMC4404944 DOI: 10.3389/fimmu.2015.00182] [Citation(s) in RCA: 191] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 04/02/2015] [Indexed: 12/17/2022] Open
Abstract
The cell-surface glycoprotein CD44 is involved in a multitude of important physiological functions including cell proliferation, adhesion, migration, hematopoiesis, and lymphocyte activation. The diverse physiological activity of CD44 is manifested in the pathology of a number of diseases including cancer, arthritis, bacterial and viral infections, interstitial lung disease, vascular disease, and wound healing. This diversity in biological activity is conferred by both a variety of distinct CD44 isoforms generated through complex alternative splicing, posttranslational modifications (e.g., N- and O-glycosylation), interactions with a number of different ligands, and the abundance and spatial distribution of CD44 on the cell surface. The extracellular matrix glycosaminoglycan hyaluronic acid (HA) is the principle ligand of CD44. This review focuses both CD44-hyaluronan dependent and independent CD44 signaling and the role of CD44–HA interaction in various pathophysiologies. The review also discusses recent advances in novel treatment strategies that exploit the CD44–HA interaction either for direct targeting or for drug delivery.
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Affiliation(s)
- Andre R Jordan
- Sheila and David Fuente Program in Cancer Biology, University of Miami-Miller School of Medicine , Miami, FL , USA
| | - Ronny R Racine
- Department of Urology, University of Miami-Miller School of Medicine , Miami, FL , USA
| | - Martin J P Hennig
- Department of Urology, University of Miami-Miller School of Medicine , Miami, FL , USA ; Department of Urology and Uro-oncology, Hannover Medical School , Hannover , Germany
| | - Vinata B Lokeshwar
- Department of Urology, University of Miami-Miller School of Medicine , Miami, FL , USA ; Department of Cell Biology, University of Miami-Miller School of Medicine , Miami, FL , USA ; Miami Clinical Translational Institute, University of Miami-Miller School of Medicine , Miami, FL , USA
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Development of pathological diagnostics of human kidney cancer by multiple staining using new fluorescent Fluolid dyes. BIOMED RESEARCH INTERNATIONAL 2014; 2014:437871. [PMID: 24995295 PMCID: PMC4065777 DOI: 10.1155/2014/437871] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Accepted: 05/20/2014] [Indexed: 12/18/2022]
Abstract
New fluorescent Fluolid dyes have advantages over others such as stability against heat, dryness, and excess light. Here, we performed simultaneous immunostaining of renal tumors, clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, acquired cystic disease-associated RCC (ACD-RCC), and renal angiomyolipoma (AML), with primary antibodies against Kank1, cytokeratin 7 (CK7), and CD10, which were detected with secondary antibodies labeled with Fluolid-Orange, Fluolid-Green, and Alexa Fluor 647, respectively. Kank1 was stained in normal renal tubules, papillary RCC, and ACD-RCC, and weakly or negatively in all other tumors. CK7 was positive in normal renal tubules, papillary RCC, and ACD-RCC. In contrast, CD10 was expressed in renal tubules and clear cell RCC, papillary RCC, AML, and AC-RCC, and weakly in chromophobe RCC. These results may contribute to differentiating renal tumors and subtypes of RCCs. We also examined the stability of fluorescence and found that fluorescent images of Fluolid dyes were identical between a tissue section and the same section after it was stored for almost three years at room temperature. This indicates that tissue sections can be stored at room temperature for a relatively long time after they are stained with multiple fluorescent markers, which could open a door for pathological diagnostics.
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Blenman KRM, Lee PP. Quantitative and spatial image analysis of tumor and draining lymph nodes using immunohistochemistry and high-resolution multispectral imaging to predict metastasis. Methods Mol Biol 2014; 1102:601-621. [PMID: 24259001 DOI: 10.1007/978-1-62703-727-3_32] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Immunohistochemistry is an essential tool for clinical and translational research laboratories. It is mostly used as a qualitative measure of morphology and cell types within tissue. We have developed a high-resolution multispectral imaging method to expand the uses of immunohistochemistry by making it quantitative. In this chapter we describe the technology, both hardware and software, that we use for this method and give examples of applications.
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Affiliation(s)
- Kim R M Blenman
- Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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21
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Gdowski A, Ranjan AP, Mukerjee A, Vishwanatha JK. Nanobiosensors: role in cancer detection and diagnosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 807:33-58. [PMID: 24619617 DOI: 10.1007/978-81-322-1777-0_4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The ability to detect many cancers at an early stage in its clinical course has the potential to improve patient outcomes in terms of morbidity and mortality. Nanosized components incorporated into existing clinical diagnostic and detection systems as well as novel nanobiosensors have demonstrated improved sensitivity and specificity compared with traditional cancer testing approaches. Nanoparticles, nanowires, nanotubes, and nanocantilevers are examples of four nanobiosensor systems that have been used experimentally in the context of detection and diagnosis of prostate, breast, pancreatic, lung, and brain cancers over the past few years. Nanobiosensors will begin to transition into clinically validated tests as experimental and engineering techniques advance. This paper presents examples of some such nanobiosensors for cancer diagnosis and detection.
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Affiliation(s)
- Andrew Gdowski
- Department of Molecular Biology and Immunology, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
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Abstract
The field of anatomic pathology has changed significantly over the last decades and, as a result of the technological developments in molecular pathology and genetics, has had increasing pressures put on it to become quantitative and to provide more information about protein expression on a cellular level in tissue sections. Multispectral imaging (MSI) has a long history as an advanced imaging modality and has been used for over a decade now in pathology to improve quantitative accuracy, enable the analysis of multicolor immunohistochemistry, and drastically reduce the impact of contrast-robbing tissue autofluorescence common in formalin-fixed, paraffin-embedded tissues. When combined with advanced software for the automated segmentation of different tissue morphologies (eg, tumor vs stroma) and cellular and subcellular segmentation, MSI can enable the per-cell quantitation of many markers simultaneously. This article covers the role that MSI has played in anatomic pathology in the analysis of formalin-fixed, paraffin-embedded tissue sections, discusses the technological aspects of why MSI has been adopted, and provides a review of the literature of the application of MSI in anatomic pathology.
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Abstract
Cancer stem cells (CSCs) have been proposed as the driving force of tumorigenesis and the seeds of metastases. However, their existence and role remain a topic of intense debate. Recently, the identification of CSCs in endogenously developing mouse tumours has provided further support for this concept. Here I discuss the challenges in identifying CSCs, their dependency on a supportive niche and their role in metastasis, and propose that stemness is a flexible — rather than fixed — quality of tumour cells that can be lost and gained.
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Affiliation(s)
- Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
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Noninvasive identification of viable cell populations in docetaxel-treated breast tumors using ferritin-based magnetic resonance imaging. PLoS One 2013; 8:e52931. [PMID: 23301003 PMCID: PMC3534651 DOI: 10.1371/journal.pone.0052931] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Accepted: 11/22/2012] [Indexed: 12/01/2022] Open
Abstract
Background Cancer stem cells (CSCs) are highly tumorigenic and are responsible for tumor progression and chemoresistance. Noninvasive imaging methods for the visualization of CSC populations within tumors in vivo will have a considerable impact on the development of new CSC-targeting therapeutics. Methodology/Principal Findings In this study, human breast cancer stem cells (BCSCs) transduced with dual reporter genes (human ferritin heavy chain [FTH] and enhanced green fluorescence protein [EGFP]) were transplanted into NOD/SCID mice to allow noninvasive tracking of BCSC-derived populations. No changes in the properties of the BCSCs were observed due to ferritin overexpression. Magnetic resonance imaging (MRI) revealed significantly different signal intensities (R2* values) between BCSCs and FTH-BCSCs in vitro and in vivo. In addition, distinct populations of pixels with high R2* values were detected in docetaxel-treated FTH-BCSC tumors compared with control tumors, even before the tumor sizes changed. Histological analysis revealed that areas showing high R2* values in docetaxel-treated FTH-BCSC tumors by MRI contained EGFP+/FTH+ viable cell populations with high percentages of CD44+/CD24− cells. Conclusions/Significance These findings suggest that ferritin-based MRI, which provides high spatial resolution and tissue contrast, can be used as a reliable method to identify viable cell populations derived from BCSCs after chemotherapy and may serve as a new tool to monitor the efficacy of CSC-targeting therapies in vivo.
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Tabatabaei-Panah AS, Jeddi-Tehrani M, Ghods R, Akhondi MM, Mojtabavi N, Mahmoudi AR, Mirzadegan E, Shojaeian S, Zarnani AH. Accurate sensitivity of quantum dots for detection of HER2 expression in breast cancer cells and tissues. J Fluoresc 2012; 23:293-302. [PMID: 23212129 DOI: 10.1007/s10895-012-1147-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2012] [Accepted: 11/06/2012] [Indexed: 10/27/2022]
Abstract
Here we introduce novel optical properties and accurate sensitivity of Quantum dot (QD)-based detection system for tracking the breast cancer marker, HER2. QD525 was used to detect HER2 using home-made HER2-specific monoclonal antibodies in fixed and living HER2(+) SKBR-3 cell line and breast cancer tissues. Additionally, we compared fluorescence intensity (FI), photostability and staining index (SI) of QD525 signals at different exposure times and two excitation wavelengths with those of the conventional organic dye, FITC. Labeling signals of QD525 in both fixed and living breast cancer cells and tissue preparations were found to be significantly higher than those of FITC at 460-495 nm excitation wavelengths. Interestingly, when excited at 330-385 nm, the superiority of QD525 was more highlighted with at least 4-5 fold higher FI and SI compared to FITC. Moreover, QDs exhibited exceptional photostability during continuous illumination of cancerous cells and tissues, while FITC signal faded very quickly. QDs can be used as sensitive reporters for in situ detection of tumor markers which in turn could be viewed as a novel approach for early detection of cancers. To take comprehensive advantage of QDs, it is necessary that their optimal excitation wavelength is employed.
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Affiliation(s)
- Akram-Sadat Tabatabaei-Panah
- Department of Biology, Faculty of Basic Sciences, Islamic Azad University, East Tehran Branch (Ghiamdasht), Tehran, Iran
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Lu S, Labhasetwar V. Drug Resistant Breast Cancer Cell Line Displays Cancer Stem Cell Phenotype and Responds Sensitively to Epigenetic Drug SAHA. Drug Deliv Transl Res 2012; 3:183-94. [PMID: 23543868 DOI: 10.1007/s13346-012-0113-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancer stem cell (CSC) population in solid human breast tumor was identified by CD44(+)/CD24(-) phenotype, characterized by high tumorigenicity, invasiveness and drug resistance. In this study, we characterized drug resistant breast cancer cell line-MCF-7/Adr and a number of breast cancer cell lines using flow cytometry, immunofluorescence, mammosphere formation assay and migration assay, examining their CSC immunophenotypes, presence of CSC proteins, tumorigenicity in vitro and migratory rates, respectively. Our results show that MCF-7/Adr cells uniformly display CSC characteristics yet retain low migratory rate. They are also able to self-renew and differentiate under floating culture conditions. Furthermore, MCF-7/Adr is selectively sensitive to epigenetic drug, suberoylanilide hydroxamic acid (SAHA), losing drug resistance and changes morphology yet retaining CSC immunophenotypes. In conclusion, we show that resistant breast cancer cell line MCF-7/Adr demonstrates uniform CSC like characteristics and are sensitive to epigenetic drug treatment.
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Affiliation(s)
- Shan Lu
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195 ; University of Akron, Integrated Bioscience Program, Akron, Ohio, 44325
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Hahne JC, Honig A, Meyer SR, Gambaryan S, Walter U, Wischhusen J, Häussler SFM, Segerer SE, Fujita N, Dietl J, Engel JB. Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro. Oncol Rep 2012; 28:2023-8. [PMID: 22992944 DOI: 10.3892/or.2012.2041] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Accepted: 05/24/2012] [Indexed: 11/06/2022] Open
Abstract
Platinum resistance is the most crucial problem for treatment of ovarian cancer. Increasing evidence points towards AKT overexpression as a mechanistic reason for this clinical condition. The present study evaluates the effect of overexpression and downregulation of AKT on the sensitivity to cisplatin in a platinum-resistant human ovarian cancer cell line and the corresponding platinum-sensitive parental cell line. A2780 and A2780cis ovarian cancer cell lines were stably transfected with an AKT-sense and AKT-antisense plasmid. Successful transfection was evaluated by western blot analysis. Cytotoxic effects of cisplatin were evaluated by metabolic (MTT) and clonogenicity assays as well as by FACS analysis. AKT overexpression (confirmed by western blotting) converted platinum-sensitive A2780 into platinum-resistant cells as shown by MTT assay. Importantly, platinum resistance of A2780cis cells could be reversed by downregulation of AKT, as demonstrated by MTT and clonogenicity assays and FACS analysis. Our data provide strong evidence that cisplatin resistance in ovarian cancer is mediated by AKT overexpression and can be overcome by AKT downregulation, thus, providing a rationale for clinical phase II/III studies combining AKT inhibitors with cisplatin.
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Affiliation(s)
- J C Hahne
- Department of Gynecology, University of Würzburg, D-97080 Würzburg, Germany
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Perrone G, Gaeta LM, Zagami M, Nasorri F, Coppola R, Borzomati D, Bartolozzi F, Altomare V, Trodella L, Tonini G, Santini D, Cavani A, Muda AO. In situ identification of CD44+/CD24- cancer cells in primary human breast carcinomas. PLoS One 2012; 7:e43110. [PMID: 23028444 PMCID: PMC3441535 DOI: 10.1371/journal.pone.0043110] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2011] [Accepted: 07/17/2012] [Indexed: 12/31/2022] Open
Abstract
Breast cancer cells with the CD44+/CD24− phenotype have been reported to be tumourigenic due to their enhanced capacity for cancer development and their self-renewal potential. The identification of human tumourigenic breast cancer cells in surgical samples has recently received increased attention due to the implications for prognosis and treatment, although limitations exist in the interpretation of these studies. To better identify the CD44+/CD24− cells in routine surgical specimens, 56 primary breast carcinoma cases were analysed by immunofluorescence and confocal microscopy, and the results were compared using flow cytometry analysis to correlate the amount and distribution of the CD44+/CD24− population with clinicopathological features. Using these methods, we showed that the breast carcinoma cells displayed four distinct sub-populations based on the expression pattern of CD44 and CD24. The CD44+/CD24− cells were found in 91% of breast tumours and constituted an average of 6.12% (range, 0.11%–21.23%) of the tumour. A strong correlation was found between the percentage of CD44+/CD24− cells in primary tumours and distant metastasis development (p = 0.0001); in addition, there was an inverse significant association with ER and PGR status (p = 0.002 and p = 0.001, respectively). No relationship was evident with tumour size (T) and regional lymph node (N) status, differentiation grade, proliferative index or HER2 status. In a multivariate analysis, the percentage of CD44+/CD24− cancer cells was an independent factor related to metastasis development (p = 0.004). Our results indicate that confocal analysis of fluorescence-labelled breast cancer samples obtained at surgery is a reliable method to identify the CD44+/CD24− tumourigenic cell population, allowing for the stratification of breast cancer patients into two groups with substantially different relapse rates on the basis of CD44+/CD24− cell percentage.
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Affiliation(s)
- Giuseppe Perrone
- Department of Pathology, Campus Bio-Medico University of Rome, Rome, Italy
| | - Laura Maria Gaeta
- Department of Pathology, Campus Bio-Medico University of Rome, Rome, Italy
| | - Mariagiovanna Zagami
- Department of Pathology, Campus Bio-Medico University of Rome, Rome, Italy
- Department of Pathology, Ospedale S. Maria della Misericordia, Udine, Italy
| | | | - Roberto Coppola
- Department of Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Domenico Borzomati
- Department of Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | | | | | - Lucio Trodella
- Radiotherapy Unit, Campus Bio-Medico University of Rome, Rome, Italy
| | - Giuseppe Tonini
- Oncology Unit, Campus Bio-Medico University of Rome, Rome, Italy
| | - Daniele Santini
- Oncology Unit, Campus Bio-Medico University of Rome, Rome, Italy
| | | | - Andrea Onetti Muda
- Department of Pathology, Campus Bio-Medico University of Rome, Rome, Italy
- * E-mail:
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Chen C, Peng J, Sun SR, Peng CW, Li Y, Pang DW. Tapping the potential of quantum dots for personalized oncology: current status and future perspectives. Nanomedicine (Lond) 2012; 7:411-28. [PMID: 22385199 DOI: 10.2217/nnm.12.9] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cancer is one of the most serious health threats worldwide. Personalized oncology holds potential for future cancer care in clinical practice, where each patient could be delivered individualized medicine on the basis of key biological features of an individual tumor. One of the most urgent problems is to develop novel approaches that incorporate the increasing molecular information into the understanding of cancer biological behaviors for personalized oncology. Quantum dots are a heterogeneous class of engineered fluorescent nanoparticles with unique optical and chemical properties, which make them promising platforms for biomedical applications. With the unique optical properties, the utilization of quantum dot-based nanotechnology has been expanded into a wide variety of attractive biomedical applications for cancer diagnosis, monitoring, pathogenesis, treatment, molecular pathology and heterogeneity in combination with cancer biomarkers. Here, we focus on the clinical application of quantum dot-based nanotechnology in personalized oncology, covering topics on individualized cancer diagnosis and treatment by in vitro and in vivo molecular imaging technologies, and in-depth understanding of the biological behaviors of tumors from a nanotechnology perspective. In addition, the major challenges in translating quantum dot-based nanotechnology into clinical application and promising future directions in personalized oncology are also discussed.
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Affiliation(s)
- Chuang Chen
- Department of Oncology, Zhongnan Hospital of Wuhan University & Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, No 169 Donghu Road, Wuchang District, Wuhan 430071, PR China
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Cancer stem cell markers in breast neoplasias: their relevance and distribution in distinct molecular subtypes. Virchows Arch 2012; 460:545-53. [PMID: 22562130 DOI: 10.1007/s00428-012-1237-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Revised: 03/29/2012] [Accepted: 04/10/2012] [Indexed: 12/26/2022]
Abstract
The identification and characterization of cancer stem cells might lead to more effective control of neoplastic disease, by directing therapies to the most aggressive cells. For that reason, the identification of cancer stem cells (CSCs) in breast tumours is one of the priorities in breast cancer research, which has resulted in many studies attempting to identify their presence based on the expression of specific molecular markers. In this review, we describe the main molecular markers that have been identified as being able to recognise CSCs in breast carcinomas, the major molecular pathways that regulate CSCs and their association with the different molecular subtypes.
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Han JP, Liu B, Yang YL, Su QJ, Shi M, Qian Z, Dong L, Zhang CL, Ha YD. Relationship between characteristics of CD44 +/ki-67 - colorectal cancer stem cells and clinicopathological characteristics in patients with colorectal cancer. Shijie Huaren Xiaohua Zazhi 2011; 19:3483-3488. [DOI: 10.11569/wcjd.v19.i34.3483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the number, location, distribution and staining features of CD44+/ki-67- colorectal cancer stem cells and to analyze their relation with clinicopathological characteristics in patients with colorectal carcinoma.
METHODS: Streptavidin-HRP immunohistochemical staining, double immunohistochemical staining and hematoxylin-eosin staining were performed to detect the expression of CD44 and ki-67 in 10 cases of normal mucosal tissue, 15 cases of adenoma with atypical hyperplasia, 59 cases of colorectal carcinoma, and human colon cancer cell line SW620. The number, location, distribution and staining features of CD44+/ki-67- colorectal cancer stem cells were observed, and their relation with clinicopathological characteristics was analyzed.
RESULTS: The number of CD44+/ki-67- tumor cells accounted for 0.1%-25.0% (average 5.82%) of all tumor cells, and the cells were mainly distributed in the sides of the basal membrane or common wall of glands. These cells had round or oval nuclei that were consistent in size, and contained deep stained chromatin and less cytoplasm. These features are consistent with those of stem cells in the intestinal crypts. The number of CD44+/ki-67- tumor cells was significantly correlated with depth of cancer infiltration (χ2 = 1.851, P < 0.05) and lymph node metastasis (χ2 = -4.113, P < 0.01).
CONCLUSION: CD44+/ki-67- are suitable specific markers for tumor stem cells and can be used for tumor stem cell isolation, targeted therapy, individualized treatment, prediction of tumor metastasis, and estimation of prognosis in patients with colorectal cancer.
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Steponkiene S, Kavaliauskiene S, Purviniene R, Rotomskis R, Juzenas P. Quantum dots affect expression of CD133 surface antigen in melanoma cells. Int J Nanomedicine 2011; 6:2437-44. [PMID: 22072879 PMCID: PMC3205138 DOI: 10.2147/ijn.s24477] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND In novel treatment approaches, therapeutics should be designed to target cancer stem cells (CSCs). Quantum dots (QDs) are a promising new tool in fighting against cancer. However, little is known about accumulation and cytotoxicity of QDs in CSCs. METHODS Accumulation and cytotoxicity of CdTe-MPA (mercaptopropionic acid) QDs in CSCs were assessed using flow cytometry and fluorescence-activated cell sorting techniques as well as a colorimetric cell viability assay. RESULTS We investigated the expression of two cell surface-associated glycoproteins, CD44 and CD133, in four different cancer cell lines (glioblastoma, melanoma, pancreatic, and prostate adenocarcinoma). Only the melanoma cells were positive to both markers of CD44 and CD133, whereas the other cells were only CD44-positive. The QDs accumulated to a similar extent in all subpopulations of the melanoma cells. The phenotypical response after QD treatment was compared with the response after ionizing radiation treatment. The percentage of the CD44(high-)CD133(high) subpopulation decreased from 72% to 55%-58% for both treatments. The stem-like subpopulation CD44(high)CD133(low/-) increased from 26%-28% in the untreated melanoma cells to 36%-40% for both treatments. CONCLUSION Treatment of melanoma cells with QDs results in an increase of stem-like cell subpopulations. The changes in phenotype distribution of the melanoma cells after the treatment with QDs are comparable with the changes after ionizing radiation.
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Affiliation(s)
- Simona Steponkiene
- Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Radiumhospital, Oslo, Norway
- Faculty of Natural Sciences, Vilnius University, Vilnius, Lithuania
- Biomedical Physics Laboratory of Oncology Institute, Vilnius University, Vilnius, Lithuania
| | - Simona Kavaliauskiene
- Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Radiumhospital, Oslo, Norway
| | - Rasa Purviniene
- Immunology Laboratory of Oncology Institute, Vilnius University, Vilnius, Lithuania
| | - Ricardas Rotomskis
- Biomedical Physics Laboratory of Oncology Institute, Vilnius University, Vilnius, Lithuania
- Biophotonics Laboratory, Laser Research Center, Vilnius University, Vilnius, Lithuania
| | - Petras Juzenas
- Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Radiumhospital, Oslo, Norway
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Zacheo A, Quarta A, Mangoni A, Pompa PP, Mastria R, Capogrossi MC, Rinaldi R, Pellegrino T. CdSe/CdS Semiconductor Quantum Rods as Robust Fluorescent Probes for Paraffin-Embedded Tissue Imaging. IEEE Trans Nanobioscience 2011; 10:209-15. [DOI: 10.1109/tnb.2011.2166404] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Tan A, Yildirimer L, Rajadas J, De La Peña H, Pastorin G, Seifalian A. Quantum dots and carbon nanotubes in oncology: a review on emerging theranostic applications in nanomedicine. Nanomedicine (Lond) 2011; 6:1101-14. [DOI: 10.2217/nnm.11.64] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Cancer is one of the main causes of death in the world, and according to the WHO it is projected to continue rising. Current diagnostic modalities for the detection of cancer include the use of x-rays, magnetic resonance imaging and positron emission tomography, among others. The treatment of cancer often involves the use (or combination) of chemotherapeutic drugs, radiotherapy and interventional surgery (for solid and operable tumors). The application of nanotechnology in biology and medicine is advancing rapidly. Recent evidence suggests that quantum dots (QDs) can be used to image cancer cells as they display superior fluorescent properties compared with conventional chromophores and contrast agents. In addition, carbon nanotubes (CNTs) have emerged as viable candidates for novel chemotherapeutic drug delivery-platforms. The unique photothermal properties of CNTs also allow them to be used in conjunction with near infrared radiation and lasers to thermally ablate cancer cells. Furthermore, mounting evidence indicates that it is possible to conjugate QDs to CNTs, making it possible to exploit their novel attributes in the realm of cancer theranostics (diagnostics and therapy). Here we review the current literature pertaining to the applications of QDs and CNTs in oncology, and also discuss the relevance and implications of nanomedicine in a clinical setting.
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Affiliation(s)
- Aaron Tan
- Centre for Nanotechnology & Regenerative Medicine, UCL Division of Surgery & Interventional Science, University College London, London, UK
| | - Lara Yildirimer
- Centre for Nanotechnology & Regenerative Medicine, UCL Division of Surgery & Interventional Science, University College London, London, UK
| | - Jayakumar Rajadas
- Laboratory of Biomaterial & Advanced Drug Delivery, Department of Neurology & Neurological Sciences, Stanford University School of Medicine, CA, USA
| | - Hugo De La Peña
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Giorgia Pastorin
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore
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Ray S, Reddy PJ, Choudhary S, Raghu D, Srivastava S. Emerging nanoproteomics approaches for disease biomarker detection: a current perspective. J Proteomics 2011; 74:2660-81. [PMID: 21596164 DOI: 10.1016/j.jprot.2011.04.027] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Revised: 03/15/2011] [Accepted: 04/28/2011] [Indexed: 01/29/2023]
Abstract
Availability of genome sequence of human and different pathogens has advanced proteomics research for various clinical applications. One of the prime goals of proteomics is identification and characterization of biomarkers for cancer and other fatal human diseases to aid an early diagnosis and monitor disease progression. However, rapid detection of low abundance biomarkers from the complex biological samples under clinically relevant conditions is extremely difficult, and it requires the development of ultrasensitive, robust and high-throughput technological platform. In order to overcome several technical limitations associated with sensitivity, dynamic range, detection time and multiplexing, proteomics has started integrating several emerging disciplines such as nanotechnology, which has led to the development of a novel analytical platform known as 'nanoproteomics'. Among the diverse classes of nanomaterials, the quantum dots, gold nanoparticles, carbon nanotubes and silicon nanowires are the most promising candidates for diagnostic applications. Nanoproteomics offers several advantages such as ultralow detection, short assay time, high-throughput capability and low sample consumption. In this article, we have discussed the application of nanoproteomics for biomarker discovery in various diseases with special emphasis on various types of cancer. Furthermore, we have discussed the prospects, merits and limitations of nanoproteomics.
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Affiliation(s)
- Sandipan Ray
- Wadhwani Research Center for Biosciences and Bioengineering, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India
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Grobmyer SR, Morse DL, Fletcher B, Gutwein LG, Sharma P, Krishna V, Frost SC, Moudgil BM, Brown SC. The promise of nanotechnology for solving clinical problems in breast cancer. J Surg Oncol 2011; 103:317-325. [DOI: 10.1002/jso.21698] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Abstract
The two leading models that have been used to explain tumor progression in head and neck squamous cell carcinoma (HNSCC) are the stochastic clonal evolution model, in which many tumor cells are individually capable of recapitulating the entire tumor mass, and the cancer stem hierarchy model, in which only rare totipotential tumor stem cells can recapitulate the tumor. In this issue, Cameron et al use cell surface marker and clonal cell analyses in combination with a xenotransplant approach to provide data that support the stochastic clonal evolution model in HNSCC. This interpretation is subject, however, to limitations inherent in the experimental approach employed. Understanding the basis of tumor progression in HNSCC as well as other cancers should be further explored because of important implications for effective treatments.
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Hill R, Calvopina JH, Kim C, Wang Y, Dawson DW, Donahue TR, Dry S, Wu H. PTEN loss accelerates KrasG12D-induced pancreatic cancer development. Cancer Res 2010; 70:7114-24. [PMID: 20807812 DOI: 10.1158/0008-5472.can-10-1649] [Citation(s) in RCA: 132] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
KRAS mutations are found in ∼90% of human pancreatic ductal adenocarcinomas (PDAC). However, mice genetically engineered to express Kras(G12D) from its endogenous locus develop PDACs only after a prolonged latency, indicating that other genetic events or pathway alterations are necessary for PDAC progression. The PTEN-controlled phosphatidylinositol 3-kinase (PI3K)/AKT signaling axis is dysregulated in later stages of PDAC. To better elucidate the role of PTEN/PI3K/AKT signaling in Kras(G12D)-induced PDAC development, we crossed Pten conditional knockout mice (Pten(lox/lox)) to mice with conditional activation of Kras(G12D). The resulting compound heterozygous mutant mice showed significantly accelerated development of acinar-to-ductal metaplasia (ADM), malignant pancreatic intraepithelial neoplasia (mPanIN), and PDAC within a year. Moreover, all mice with Kras(G12D) activation and Pten homozygous deletion succumbed to cancer by 3 weeks of age. Our data support a dosage-dependent role for PTEN, and the resulting dysregulation of the PI3K/AKT signaling axis, in both PDAC initiation and progression, and shed additional light on the signaling mechanisms that lead to the development of ADM and subsequent mPanIN and pancreatic cancer.
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Affiliation(s)
- Reginald Hill
- Department of Molecular and Medical Pharmacology, University of California Los Angeles School of Medicine, CHS 23-214, 650 CE Young Drive South, Los Angeles, CA 90095, USA
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Chen C, Xia HS, Gong YP, Peng J, Peng CW, Hu MB, Zhu XB, Pang DW, Sun SR, Li Y. The quantitative detection of total HER2 load by quantum dots and the identification of a new subtype of breast cancer with different 5-year prognosis. Biomaterials 2010; 31:8818-25. [PMID: 20723971 DOI: 10.1016/j.biomaterials.2010.07.091] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2010] [Accepted: 07/26/2010] [Indexed: 10/19/2022]
Abstract
Accurate classification is fundamental for breast cancer (BC) personalized care. Current BC classification based on the either traditional morphological staging or molecular signatures seems inefficient to reveal the"true"behaviors of invasive BC evolution. An appropriate approach combining the macro- and micro-pathologic information might be more useful academically as well as clinically. Here we explore a holistic approach by integrating a key molecular prognostic indicator of BC, HER2, with quantitative determination using quantum dots (QDs)--based nanotechnology and spectral analysis, and a key macropathologic indicator, tumor size, resulting a new indicator, total HER2 load. This indicator might better reveal BC heterogeneity and new subtypes of BC with different 5-year disease-free survival compared with current methods, which could be helpful in formulating a more personalized targeted therapy for BC. Furthermore, this mode integrating macro- and micro-pathological indicators might help gain new insights into invasive BC biological behaviors.
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Affiliation(s)
- Chuang Chen
- Department of Oncology, Zhongnan Hospital of Wuhan University, No 169 Donghu Road, Wuchang District, Wuhan 430071, PR China
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