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Maravelez Acosta VA, Garcia MDLC, Patiño López G, Crisóstomo Vázquez MDP, Franco Sandoval LO, Eligio García L. Association of Neuroblastoma (NB) SH-SY5Y Cells with Antibodies of Parasitic Origin (Anti- Acanthamoeba and Anti- Toxocara canis). Int J Mol Sci 2024; 25:13577. [PMID: 39769340 PMCID: PMC11678856 DOI: 10.3390/ijms252413577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 10/27/2024] [Accepted: 10/28/2024] [Indexed: 01/11/2025] Open
Abstract
It is little known that Acanthamoeba trophozoites and Toxocara canis eggs can reduce tumors in vitro and animal models. Although this has been known for many years, the mechanism that induces the antitumor effect in these parasites is still not known. We employed Western blot (WB) and immunofluorescence (IFC) by confocal microscopy to explore the potential protein binding between neuroblastoma (NB) SH-SY5Y cells and anti-Acanthamoeba and anti-Toxocara canis antibodies. Using WB, we detected two fragments of 70 kDa and 60 kDa recognized by the anti-Acanthamoeba antibodies, and two fragments of 115 kDa and 70 kDa recognized by the anti-Toxocara canis antibodies. In both cases, the IFC results were positive in the cell membrane of the SH-SY5Y cells. Our findings suggest a potential overlap of similar molecules between these parasites and tumor cells, which may contribute to tumor elimination. Investigating the relationship between anti-Acanthamoeba and anti-Toxocara canis antibodies in neoplastic cells could provide evidence for the future use of these anti-parasitic antibodies in targeting NB or other cancers.
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Affiliation(s)
- Víctor Alberto Maravelez Acosta
- Laboratorio de Investigación en Parasitología, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico; (V.A.M.A.)
| | - Maria de Lourdes Caballero Garcia
- Laboratorio de Investigación en Parasitología, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico; (V.A.M.A.)
| | - Genaro Patiño López
- Unidad de Investigación en Inmunología y Proteomica, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico
| | - María del Pilar Crisóstomo Vázquez
- Laboratorio de Investigación en Parasitología, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico; (V.A.M.A.)
| | - Luz Ofelia Franco Sandoval
- Laboratorio de Investigación en Parasitología, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico; (V.A.M.A.)
| | - Leticia Eligio García
- Laboratorio de Investigación en Parasitología, Hospital Infantil de México Federico Gómez (HIMFG), Dr. Márquez 162. Col Doctores, Cuauhtémoc, México City 06720, Mexico; (V.A.M.A.)
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Wu R, Chen X, Chen H, Li M, Liang Y. Plasmodium infection downregulates hypoxia‑inducible factor 1α expression to suppress the vascularization and tumorigenesis of liver cancer. Oncol Lett 2024; 28:604. [PMID: 39483968 PMCID: PMC11525613 DOI: 10.3892/ol.2024.14737] [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: 05/17/2024] [Accepted: 09/06/2024] [Indexed: 11/03/2024] Open
Abstract
Liver cancer is characterized by hypervascularization. Anti-angiogenic agents may normalize the tumor vasculature and improve the efficacy of other treatments. The present study aims to investigate the anti-angiogenic effect of Plasmodium infection in a mouse model of implanted liver cancer cells. HepG2 cells were injected into the left liver lobe of nude mice as a model of in situ hepatic tumorigenesis. Plasmodium yoelii parasitized erythrocytes were administered in the animal model of liver cancer to introduce Plasmodium infection. The tumor growth and microvascular density were determined in the presence or absence of Plasmodium infection. The expression levels of hypoxia-inducible factor 1α (HIF-1α) and angiogenesis-related factors were evaluated using western blotting and reverse transcription-quantitative PCR analysis. The results demonstrated that Plasmodium infection suppressed tumor growth and vascularization in the mouse model of implanted HepG2 cells. Plasmodium parasites reduced the expression of pro-angiogenic factors (vascular endothelial growth factor A and angiopoietin 2), matrix metalloproteinases [(MMP)2 and MMP9] and inflammatory cytokines [tumor necrosis factor α, interleukin 6 (IL)-6) and IL-1β] in both hepatic and tumor tissues. HIF-1α was downregulated in both hepatic and tumor tissues upon Plasmodium infection, and HIF-1α overexpression rescued angiogenesis and tumor growth under the condition of Plasmodium infection. In conclusion, the results of the present study demonstrated the anti-angiogenic and anti-tumorigenic effects of Plasmodium infection on liver cancer through downregulating HIF-1α expression, indicating that Plasmodium parasites could be developed as an intervention strategy to restrain neo-angiogenesis in liver cancer.
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Affiliation(s)
- Runling Wu
- Department of Geriatric Respiratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Xiao Chen
- Department of Medical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Huan Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Mei Li
- Department of Clinical Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Yun Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
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Das A, Suar M, Reddy K. Hormones in malaria infection: influence on disease severity, host physiology, and therapeutic opportunities. Biosci Rep 2024; 44:BSR20240482. [PMID: 39492784 PMCID: PMC11581842 DOI: 10.1042/bsr20240482] [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: 09/08/2024] [Revised: 11/01/2024] [Accepted: 11/01/2024] [Indexed: 11/05/2024] Open
Abstract
Human malaria, caused by Plasmodium parasites, is a fatal disease that disrupts the host's physiological balance and affects the neuroendocrine system. This review explores how malaria influences and is influenced by hormones. Malaria activates the Hypothalamus-Pituitary-Adrenal axis, leading to increased cortisol, aldosterone, and epinephrine. Cortisol, while reducing inflammation, aids parasite survival, whereas epinephrine helps manage hypoglycemia. The Hypothalamus-Pituitary-Gonad and Hypothalamus-Pituitary-Thyroid axes are also impacted, resulting in lower sex and thyroid hormone levels. Malaria disrupts the renin-angiotensin-aldosterone system (RAAS), causing higher angiotensin-II and aldosterone levels, contributing to edema, hyponatremia and hypertension. Malaria-induced anemia is exacerbated by increased hepcidin, which impairs iron absorption, reducing both iron availability for the parasite and red blood cell formation, despite elevated erythropoietin. Hypoglycemia is common due to decreased glucose production and hyperinsulinemia, although some cases show hyperglycemia due to stress hormones and inflammation. Hypocalcemia, and hypophosphatemia are associated with low Vitamin D3 and parathyroid hormone but high calcitonin. Hormones such as DHEA, melatonin, PTH, Vitamin D3, hepcidin, progesterone, and erythropoietin protects against malaria. Furthermore, synthetic analogs, receptor agonists and antagonists or mimics of hormones like DHEA, melatonin, serotonin, PTH, vitamin D3, estrogen, progesterone, angiotensin, and somatostatin are being explored as potential antimalarial treatments or adjunct therapies. Additionally, hormones like leptin and PCT are being studied as probable markers of malaria infection.
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Affiliation(s)
- Aleena Das
- School of Biotechnology, Kalinga Institute of Industrial Technology (Deemed University), Bhubaneswar, 751024, India
| | - Mrutyunjay Suar
- School of Biotechnology, Kalinga Institute of Industrial Technology (Deemed University), Bhubaneswar, 751024, India
- Technology Business Incubator, Kalinga Institute of Industrial Technology (Deemed University), Bhubaneswar, 751024, India
| | - K Sony Reddy
- School of Biotechnology, Kalinga Institute of Industrial Technology (Deemed University), Bhubaneswar, 751024, India
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Eissa MM, Salem AE, El Skhawy N. Parasites revive hope for cancer therapy. Eur J Med Res 2024; 29:489. [PMID: 39367471 PMCID: PMC11453045 DOI: 10.1186/s40001-024-02057-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 09/10/2024] [Indexed: 10/06/2024] Open
Abstract
Parasites have attained a life-long stigma of being detrimental organisms with deleterious outcomes. Yet, recently, a creditable twist was verified that can dramatically change our perception of those parasites from being a source of misery to millions of people to a useful anti-cancerous tool. Various parasites have shown promise to combat cancer in different experimental models, including colorectal, lung, and breast cancers, among others. Helminths and protozoan parasites, as well as their derivatives such as Echinococcus granulosus protein KI-1, Toxoplasma gondii GRA15II, and Trypanosoma cruzi calreticulin, have demonstrated the ability to inhibit tumor growth, angiogenesis, and metastasis. This article provides an overview of the literature on various cancer types that have shown promising responses to parasite therapy in both in vitro and in vivo animal studies. Parasites have shown anti-neoplastic activity through a variety of mechanisms that collectively contribute to their anti-cancer properties. These include immunomodulation, inhibition of angiogenesis, and molecular mimicry with cancer cells. This review article sheds light on this intriguing emerging field and emphasizes the value of collaborative multidisciplinary research projects with funding agencies and pharmaceutical companies. Thus, these strategies would secure continuous exploration of this new avenue and accelerate the advancement of cancer therapy research. Although experimental studies are heavily conducted by leaps and bounds, further steps are definitely lagging. Upgrading research from the experimental level to the clinical trial would be a wise progression toward efficient exploitation of the anti-neoplastic capabilities of parasites, ultimately saving countless lives.
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Affiliation(s)
- Maha M Eissa
- Department of Medical Parasitology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
| | - Ahmed Ebada Salem
- Department of Radiology and Nuclear Medicine, School of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 48123, USA
| | - Nahla El Skhawy
- Department of Medical Parasitology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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Xie Y, Wang J, Wang Y, Wen Y, Pu Y, Wang B. Parasite-enhanced immunotherapy: transforming the "cold" tumors to "hot" battlefields. Cell Commun Signal 2024; 22:448. [PMID: 39327550 PMCID: PMC11426008 DOI: 10.1186/s12964-024-01822-4] [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: 07/05/2024] [Accepted: 09/08/2024] [Indexed: 09/28/2024] Open
Abstract
Immunotherapy has emerged as a highly effective treatment for various tumors. However, the variable response rates associated with current immunotherapies often restrict their beneficial impact on a subset of patients. Therefore, more effective treatment approaches that can broaden the scope of therapeutic benefits to a larger patient population are urgently needed. Studies have shown that some parasites and their products, for example, Plasmodium, Toxoplasma, Trypanosoma, and Echinococcus, can effectively transform "cold" tumors into "hot" battlefields and reshape the tumor microenvironment, thereby stimulating innate and adaptive antitumor immune responses. These parasitic infections not only achieve the functional reversal of innate immune cells, such as neutrophils, macrophages, myeloid-derived suppressor cells, regulatory T cells, and dendritic cells, in tumors but also successfully activate CD4+/CD8+ T cells and even B cells to produce antibodies, ultimately resulting in an antitumor-specific immune response and antibody-dependent cellular cytotoxicity. Animal studies have confirmed these findings. This review discusses the abovementioned content and the challenges faced in the future clinical application of antitumor treatment strategies based on parasitic infections. With the potential of these parasites and their byproducts to function as anticancer agents, we anticipate that further investigations in this field could yield significant advancements in cancer treatment.
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Affiliation(s)
- Yujun Xie
- Laboratory of Tumor Immunobiology, Department of Public Health and Pathogen Biology, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China
- Institute of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China
- Graduate School, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Jinyan Wang
- College of Basic Medical Science, China Medical University, Shenyang, Liaoning, 110122, China
| | - Yafei Wang
- Faculty of Arts and Science, University of Toronto, Toronto, ON, M5S 3G3, Canada
| | - Yalin Wen
- Laboratory of Tumor Immunobiology, Department of Public Health and Pathogen Biology, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China
- Institute of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China
- Graduate School, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Yanping Pu
- Graduate School, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Benfan Wang
- Laboratory of Tumor Immunobiology, Department of Public Health and Pathogen Biology, College of Integrated Chinese and Western Medicine (College of Life Science), Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.
- Institute of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.
- Institute of Surgery, The First Affiliated Hospital, Anhui University of Chinese Medicine, Hefei, Anhui, 230038, China.
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Walter NS, Bhattacharyya S. Mining parasites for their potential as novel therapeutic agents against cancer. Med Oncol 2024; 41:211. [PMID: 39073638 DOI: 10.1007/s12032-024-02458-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024]
Abstract
Despite recent advances in the management and therapeutic of cancer, the treatment of the disease is limited by its high cost and severe side effects. In this scenario, there is an unmet need to identify novel treatment alternatives for this dreaded disease. Recently there is growing evidence that parasites may cause anticancer effects because of a negative correlation between parasitic infections and tumour growth despite some parasites that are known to exhibit pro-carcinogenic effects. It has been observed that parasites exert an anticancer effect either by activating the host's immune response or by secreting certain molecules that exhibit anticancer potential. The activation of the immune response by these parasitic organisms results in the inhibition of some of the hallmarks of cancer such as tumour proliferation, angiogenesis, and metastasis. This review summarizes the current advances as well as the mechanisms underlying the possible implications of this diverse group of organisms as anticancer agents.
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Affiliation(s)
- Neha Sylvia Walter
- Department of Biophysics, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, 160012, India
| | - Shalmoli Bhattacharyya
- Department of Biophysics, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, 160012, India.
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7
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Chen X. From immune equilibrium to tumor ecodynamics. Front Oncol 2024; 14:1335533. [PMID: 38807760 PMCID: PMC11131381 DOI: 10.3389/fonc.2024.1335533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 04/01/2024] [Indexed: 05/30/2024] Open
Abstract
Objectives There is no theory to quantitatively describe the complex tumor ecosystem. At the same time, cancer immunotherapy is considered a revolution in oncology, but the methods used to describe tumors and the criteria used to evaluate efficacy are not keeping pace. The purpose of this study is to establish a new theory for quantitatively describing the tumor ecosystem, innovating the methods of tumor characterization, and establishing new efficacy evaluation criteria for cancer immunotherapy. Methods Based on the mathematization of immune equilibrium theory and the establishment of immunodynamics in a previous study, the method of reverse immunodynamics was used, namely, the immune braking force was regarded as the tumor ecological force and the immune force was regarded as the tumor ecological braking force, and the concept of momentum in physics was applied to the tumor ecosystem to establish a series of tumor ecodynamic equations. These equations were used to solve the fundamental and applied problems of the complex tumor ecosystem. Results A series of tumor ecodynamic equations were established. The tumor ecological momentum equations and their component factors could be used to distinguish disease progression, pseudoprogression, and hyperprogression in cancer immunotherapy. On this basis, the adjusted tumor momentum equations were established to achieve the equivalence of tumor activity (including immunosuppressive activity and metabolic activity) and tumor volume, which could be used to calculate individual disease remission rate and establish new efficacy evaluation criteria (ieRECIST) for immunotherapy of solid tumor based on tumor ecodynamics. At the same time, the concept of moving cube-to-force square ratio and its expression were proposed to calculate the area under the curve of tumor ecological braking force of blood required to achieve an individual disease remission rate when the adjusted tumor ecological momentum was known. Conclusions A new theory termed tumor ecodynamics emphasizing both tumor activity and tumor volume is established to solve a series of basic and applied problems in the complex tumor ecosystem. It can be predicted that the future will be the era of cancer immune ecotherapy that targets the entire tumor ecosystem.
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Affiliation(s)
- Xiaoping Chen
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- CAS Lamvac (Guangzhou) Biomedical Technology Co., Ltd., Guangzhou, China
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Zheng Z, Lu X, Zhou D, Deng XF, Liu QX, Liu XB, Zhang J, Li YQ, Zheng H, Dai JG. A novel enemy of cancer: recent investigations into protozoan anti-tumor properties. Front Cell Infect Microbiol 2024; 13:1325144. [PMID: 38274735 PMCID: PMC10808745 DOI: 10.3389/fcimb.2023.1325144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 12/28/2023] [Indexed: 01/27/2024] Open
Abstract
Cancer remains a significant global health issue, despite advances in screening and treatment. While existing tumor treatment protocols such as surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy have proven effective in enhancing the prognosis for some patients, these treatments do not benefit all patients. Consequently, certain types of cancer continue to exhibit a relatively low 5-year survival rate. Therefore, the pursuit of novel tumor intervention strategies may help improve the current effectiveness of tumor treatment. Over the past few decades, numerous species of protozoa and their components have exhibited anti-tumor potential via immune and non-immune mechanisms. This discovery introduces a new research direction for the development of new and effective cancer treatments. Through in vitro experiments and studies involving tumor-bearing mice, the anti-tumor ability of Toxoplasma gondii, Plasmodium, Trypanosoma cruzi, and other protozoa have unveiled diverse mechanisms by which protozoa combat cancer, demonstrating encouraging prospects for their application. In this review, we summarize the anti-tumor ability and anti-tumor mechanisms of various protozoa and explore the potential for their clinical development and application.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Hong Zheng
- Department of Thoracic Surgery, Xinqiao Hospital, Army (Third Military) Medical University, Chongqing, China
| | - Ji-gang Dai
- Department of Thoracic Surgery, Xinqiao Hospital, Army (Third Military) Medical University, Chongqing, China
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9
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Zhang X, Yu C, Zhao S, Wang M, Shang L, Zhou J, Ma Y. The role of tumor-associated macrophages in hepatocellular carcinoma progression: A narrative review. Cancer Med 2023; 12:22109-22129. [PMID: 38098217 PMCID: PMC10757104 DOI: 10.1002/cam4.6717] [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: 04/21/2023] [Revised: 11/04/2023] [Accepted: 11/07/2023] [Indexed: 12/31/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, with complex etiology and mechanism, and a high mortality rate. Tumor-associated macrophages (TAMs) are an important part of the HCC tumor microenvironment. Studies in recent years have shown that TAMs are involved in multiple stages of HCC and are related to treatment and prognosis in HCC. The specific mechanisms between TAMs and HCC are gradually being revealed. This paper reviews recent advances in the mechanisms associated with TAMs in HCC, concentrating on an overview of effects of TAMs on drug resistance in HCC and the signaling pathways linked with HCC, providing clues for the treatment and prognosis determination of HCC.
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Affiliation(s)
- Xinyi Zhang
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Chao Yu
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Siqi Zhao
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Min Wang
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Longcheng Shang
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Jin Zhou
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Yong Ma
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
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Chen X, Tao Z, Liang Y, Ma M, Adah D, Ding W, Chen L, Li X, Dai L, Fanuel S, Zhao S, Hu W, Wu D, Duan Z, Zhou F, Qin L, Chen X, Yang Z. Plasmodium immunotherapy combined with gemcitabine has a synergistic inhibitory effect on tumor growth and metastasis in murine Lewis lung cancer models. Front Oncol 2023; 13:1181176. [PMID: 37916167 PMCID: PMC10618005 DOI: 10.3389/fonc.2023.1181176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 09/18/2023] [Indexed: 11/03/2023] Open
Abstract
Objective Our previous studies have demonstrated that Plasmodium immunotherapy (infection) has antitumor effects in mice. However, as a new form of immunotherapy, this therapy has a weakness: its specific killing effect on tumor cells is relatively weak. Therefore, we tested whether Plasmodium immunotherapy combined with gemcitabine (Gem), a representative chemotherapy drug, has synergistic antitumor effects. Methods We designed subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) models to test the antitumor effect of Plasmodium chabaudi ASS (Pc) infection in combination with Gem treatment and explored its underlying mechanisms. Results We found that both Pc infection alone and Gem treatment alone significantly inhibited tumor growth in the subcutaneous model, and combination therapy was more effective than either monotherapy. Monotherapy only tended to prolong the survival of tumor-bearing mice, while the combination therapy significantly extended the survival of mice, indicating a significant synergistic effect of the combination. In the mechanistic experiments, we found that the combination therapy significantly upregulated E-cadherin and downregulated Snail protein expression levels, thus inhibiting epithelial-mesenchymal transition (EMT) of tumor cells, which may be due to the blockade of CXCR2/TGF-β-mediated PI3K/Akt/GSK-3β signaling pathway. Conclusion The combination of Pc and Gem plays a synergistic role in inhibiting tumor growth and metastasis, and prolonging mice survival in murine lung cancer models. These effects are partially attributed to the inhibition of EMT of tumor cells, which is potentially due to the blockade of CXCR2/TGF-β-mediated PI3K/Akt/GSK-3β/Snail signaling pathway. The clinical transformation of Plasmodium immunotherapy combined with Gem for lung cancer is worthy of expectation.
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Affiliation(s)
- Xiao Chen
- Department of Medical Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
| | - Zhu Tao
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
- CAS-Lamvac (Guangzhou) Biomedical Technology Co., Ltd., Guangzhou, Guangdong, China
| | - Yun Liang
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Meng Ma
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
- The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Dickson Adah
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
| | - Wenting Ding
- CAS-Lamvac (Guangzhou) Biomedical Technology Co., Ltd., Guangzhou, Guangdong, China
| | - Lili Chen
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
| | - Xiaofen Li
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
| | - Linglin Dai
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
| | - Songwe Fanuel
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
- Department of Applied Biosciences and Biotechnology, Faculty of Science and Technology, Midlands State University, Gweru, Zimbabwe
| | - Siting Zhao
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
- CAS-Lamvac (Guangzhou) Biomedical Technology Co., Ltd., Guangzhou, Guangdong, China
| | - Wen Hu
- CAS-Lamvac (Guangzhou) Biomedical Technology Co., Ltd., Guangzhou, Guangdong, China
| | - Donghai Wu
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
| | - Ziyuan Duan
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
| | - Fang Zhou
- CAS-Lamvac (Guangzhou) Biomedical Technology Co., Ltd., Guangzhou, Guangdong, China
| | - Li Qin
- CAS-Lamvac (Guangzhou) Biomedical Technology Co., Ltd., Guangzhou, Guangdong, China
| | - Xiaoping Chen
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China
- CAS-Lamvac (Guangzhou) Biomedical Technology Co., Ltd., Guangzhou, Guangdong, China
| | - Zhaoqing Yang
- Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, Yunnan, China
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Yuan Y, Wu D, Li J, Huang D, Zhao Y, Gao T, Zhuang Z, Cui Y, Zheng DY, Tang Y. Mechanisms of tumor-associated macrophages affecting the progression of hepatocellular carcinoma. Front Pharmacol 2023; 14:1217400. [PMID: 37663266 PMCID: PMC10470150 DOI: 10.3389/fphar.2023.1217400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 06/23/2023] [Indexed: 09/05/2023] Open
Abstract
Tumor-associated macrophages (TAMs) are essential components of the immune cell stroma of hepatocellular carcinoma. TAMs originate from monocytic myeloid-derived suppressor cells, peripheral blood monocytes, and kupffer cells. The recruitment of monocytes to the HCC tumor microenvironment is facilitated by various factors, leading to their differentiation into TAMs with unique phenotypes. TAMs can directly activate or inhibit the nuclear factor-κB, interleukin-6/signal transducer and signal transducer and activator of transcription 3, Wnt/β-catenin, transforming growth factor-β1/bone morphogenetic protein, and extracellular signal-regulated kinase 1/2 signaling pathways in tumor cells and interact with other immune cells via producing cytokines and extracellular vesicles, thus affecting carcinoma cell proliferation, invasive and migratory, angiogenesis, liver fibrosis progression, and other processes to participate in different stages of tumor progression. In recent years, TAMs have received much attention as a prospective treatment target for HCC. This review describes the origin and characteristics of TAMs and their mechanism of action in the occurrence and development of HCC to offer a theoretical foundation for further clinical research of TAMs.
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Affiliation(s)
- Yi Yuan
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Dailin Wu
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jing Li
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Dan Huang
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yan Zhao
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Tianqi Gao
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Zhenjie Zhuang
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Ying Cui
- Department of Psychiatry, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Da-Yong Zheng
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Department of Hepatology, TCM-Integrated Hospital of Southern Medical University, Guangzhou, Guangdong, China
- Department of Hepatopancreatobiliary, Cancer Center, Southern Medical University, Guangzhou, Guangdong, China
| | - Ying Tang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
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12
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Niu ZS, Wang WH, Niu XJ. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J Gastroenterol 2022; 28:6433-6477. [PMID: 36569275 PMCID: PMC9782839 DOI: 10.3748/wjg.v28.i46.6433] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Department of Internal Medicine, Qingdao Shibei District People's Hospital, Qingdao 266033, Shandong Province, China
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13
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Chen X. From immune equilibrium to immunodynamics. Front Microbiol 2022; 13:1018817. [PMID: 36504800 PMCID: PMC9732466 DOI: 10.3389/fmicb.2022.1018817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 10/24/2022] [Indexed: 11/26/2022] Open
Abstract
Objective The immunology field has long been short of a universally applicable theoretical model that can quantitatively describe the immune response, and the theory of immune equilibrium (balance) is usually limited to the interpretation of the philosophical significance of immune phenomena. Therefore, it is necessary to establish a new immunological theory, namely, immunodynamic theory, to reanalyze the immune response. Methods By quantifying the immune dynamic equilibrium as the ratio of positive and negative immune power, the immune dynamic equilibrium equation was established. Then, the area under the curve of the positive and negative immune power was assumed to be equal in the whole process of immune response (regardless of correct or not), and through thought experiments based on this key hypothesis, a series of new concepts and expressions were derived, to establish a series of immunodynamic equations. Results New concepts of immune force and immune braking force and their expression equations, namely, the theoretical equations of immunodynamics, were derived through thought experiments, and the theoretical curves of immunodynamics were obtained according to these equations. Via the equivalent transformation of the theoretical equations and practical calculation of functional data, and by the methods of curve comparison and fitting, some practical equations of immunodynamics were established, and these practical equations were used to solve theoretical and practical problems that are related to the immunotherapy of infectious diseases and cancers. Conclusion The traditional theory of immune equilibrium has been mathematized and transformed from a philosophical category into a new concrete scientific theory, namely the theory of immunodynamics, which solves the dilemma that the traditional theory cannot guide individualized medical practice for a long time. This new theory may develop into one of the core theories of immunology in the future.
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Affiliation(s)
- Xiaoping Chen
- State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- CAS Lamvac (Guangzhou) Biomedical Technology Co., Ltd., Guangzhou, China
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14
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Preclinical Study of Plasmodium Immunotherapy Combined with Radiotherapy for Solid Tumors. Cells 2022; 11:cells11223600. [PMID: 36429033 PMCID: PMC9688403 DOI: 10.3390/cells11223600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/26/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Immune checkpoint blockade therapy (ICB) is ineffective against cold tumors and, although it is effective against some hot tumors, drug resistance can occur. We have developed a Plasmodium immunotherapy (PI) that can overcome these shortcomings. However, the specific killing effect of PI on tumor cells is relatively weak. Radiotherapy (RT) is known to have strong specific lethality to tumor cells. Therefore, we hypothesized that PI combined with RT could produce synergistic antitumor effects. We tested our hypothesis using orthotopic and subcutaneous models of mouse glioma (GL261, a cold tumor) and a subcutaneous model of mouse non-small cell lung cancer (NSCLC, LLC, a hot tumor). Our results showed that, compared with each monotherapy, the combination therapy more significantly inhibited tumor growth and extended the life span of tumor-bearing mice. More importantly, the combination therapy could cure approximately 70 percent of glioma. By analyzing the immune profile of the tumor tissues, we found that the combination therapy was more effective in upregulating the perforin-expressing effector CD8+ T cells and downregulating the myeloid-derived suppressor cells (MDSCs), and was thus more effective in the treatment of cancer. The clinical transformation of PI combined with RT in the treatment of solid tumors, especially glioma, is worthy of expectation.
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15
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Anti-Tumor Effect of Parasitic Protozoans. Bioengineering (Basel) 2022; 9:bioengineering9080395. [PMID: 36004920 PMCID: PMC9405343 DOI: 10.3390/bioengineering9080395] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/12/2022] [Accepted: 08/12/2022] [Indexed: 11/22/2022] Open
Abstract
The immune system may aberrantly silence when against “altered self”, which consequently may develop into malignancies. With the development of tumor immunology and molecular biology, the deepened understanding of the relationship between parasites and tumors shifts the attitude towards parasitic pathogens from elimination to utilization. In recent years, the antitumor impact implemented by protozoan parasites and the derived products has been confirmed. The immune system is activated and enhanced by some protozoan parasites, thereby inhibiting tumor growth, angiogenesis, and metastasis in many animal models. In this work, we reviewed the available information on the antitumor effect of parasitic infection or induced by parasitic antigen, as well as the involved immune mechanisms that modulate cancer progression. Despite the fact that clinical trials of the protozoan parasites against tumors are limited and the specific mechanisms of the effect on tumors are not totally clear, the use of genetically modified protozoan parasites and derived molecules combined with chemotherapy could be an important element for promoting antitumor treatment in the future.
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16
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Shu X, Nie Z, Luo W, Zheng Y, Han Z, Zhang H, Xia Y, Deng H, Li F, Wang S, Zhao J, He L. Babesia microti Infection Inhibits Melanoma Growth by Activating Macrophages in Mice. Front Microbiol 2022; 13:862894. [PMID: 35814662 PMCID: PMC9257138 DOI: 10.3389/fmicb.2022.862894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/31/2022] [Indexed: 11/29/2022] Open
Abstract
Babesia microti is an obligate intraerythrocytic protozoan transmitted by an Ixodes tick. Infections caused by protozoa, including Plasmodium yoelii and Toxoplasma gondii, are shown to inhibit tumor development by activating immune responses. Th1 immune response and macrophages not only are essential key factors in Babesia infection control but also play an important role in regulating tumor development. In this study, we investigated the effects of B. microti infection on melanoma in tumor-bearing mice. The results showed that B. microti infection could inhibit the growth of melanoma, significantly enlarge the spleen size (p ≤ 0.0001), and increase the survival period (over 7 days) of tumor-bearing mice. Mouse spleen immune cell analysis revealed that B. microti-infected tumor-bearing mice could increase the number of macrophages and CD4+ T cells, as well as the proportion of CD4+ T cells and M1 macrophages in the tumor. Immunohistochemical assays showed that B. microti infection could inhibit tumor angiogenesis (p ≤ 0.0032). Meanwhile, both B. microti-infected erythrocytes and culture supernatant were observed to significantly (p ≤ 0.0021) induce the mRNA expression of iNOS, IL-6, and TNF-α in macrophages. Moreover, B. microti culture supernatant could also repolarize IL-4-induced M2 macrophages to the M1 type. Overall, B. microti exerted antitumor effects by stimulating the immune system of tumor-bearing mice and inducing the polarization of immunosuppressive M2 macrophages to pro-inflammatory M1 macrophages.
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Affiliation(s)
- Xiang Shu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
| | - Zheng Nie
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
| | - Wanxin Luo
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
| | - Yaxin Zheng
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
| | - Zhen Han
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
| | - Hongyan Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
| | - Yingjun Xia
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
| | - Han Deng
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
| | - Fangjie Li
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
| | - Sen Wang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
| | - Junlong Zhao
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
- *Correspondence: Junlong Zhao,
| | - Lan He
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Animal Epidemical Disease and Infectious Zoonoses, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, China
- Lan He,
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17
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Target and drug predictions for SARS-CoV-2 infection in hepatocellular carcinoma patients. PLoS One 2022; 17:e0269249. [PMID: 35639708 PMCID: PMC9154116 DOI: 10.1371/journal.pone.0269249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/17/2022] [Indexed: 11/19/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the coronavirus disease (COVID-19), which poses a major threat to humans worldwide. With the continuous progress of the pandemic, a growing number of people are infected with SARS-CoV-2, including hepatocellular carcinoma (HCC) patients. However, the relationship between COVID-19 and HCC has not been fully elucidated. In order to provide better treatment for HCC patients infected with SARS-CoV-2, it’s urgently needed to identify common targets and find effective drugs for both. In our study, transcriptomic analysis was performed on both selected lung epithelial cell datasets of COVID-19 patients and the datasets of HCC patients to identify the synergistic effect of COVID-19 in HCC patients. What’s more, common differentially expressed genes were identified, and a protein-protein interactions network was designed. Then, hub genes and basic modules were detected based on the protein-protein interactions network. Next, functional analysis was performed using gene ontology terminology and the Kyoto Encyclopedia of Genes and Genomes pathway. Finally, protein-protein interactions revealed COVID-19 interaction with key proteins associated with HCC and further identified transcription factor (TF) genes and microRNAs (miRNA) with differentially expressed gene interactions and transcription factor activity. This study reveals that COVID-19 and HCC are closely linked at the molecular level and proposes drugs that may play an important role in HCC patients with COVID-19. More importantly, according to the results of our research, two critical drugs, Ilomastat and Palmatine, may be effective for HCC patients with COVID-19, which provides clinicians with a novel therapeutic idea when facing possible complications in HCC patients with COVID-19.
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18
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Xu Y, Wang X, Liu L, Wang J, Wu J, Sun C. Role of macrophages in tumor progression and therapy (Review). Int J Oncol 2022; 60:57. [PMID: 35362544 PMCID: PMC8997338 DOI: 10.3892/ijo.2022.5347] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
The number and phenotype of macrophages are closely related to tumor growth and prognosis. Macrophages are recruited to (and polarized at) the tumor site thereby promoting tumor growth, stimulating tumor angiogenesis, facilitating tumor cell migration, and creating a favorable environment for subsequent colonization by (and survival of) tumor cells. These phenomena contribute to the formation of an immunosuppressive tumor microenvironment (TME) and therefore speed up tumor cell proliferation and metastasis and reduce the efficacy of antitumor factors and therapies. The ability of macrophages to remodel the TME through interactions with other cells and corresponding changes in their number, activity, and phenotype during conventional therapies, as well as the association between these changes and drug resistance, make tumor-associated macrophages a new target for antitumor therapies. In this review, advantages and limitations of the existing antitumor strategies targeting macrophages in Traditional Chinese and Western medicine were analyzed, starting with the effect of macrophages on tumors and their interactions with other cells and then the role of macrophages in conventional treatments was explored. Possible directions of future developments in this field from an all-around multitarget standpoint were also examined.
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Affiliation(s)
- Yiwei Xu
- Institute of Integrated Medicine, School of Medicine, Qingdao University, Qingdao, Shandong 266073, P.R. China
| | - Xiaomin Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Lijuan Liu
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 261041, P.R. China
| | - Jia Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, P.R. China
| | - Jibiao Wu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Changgang Sun
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 261041, P.R. China
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19
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Nwabo Kamdje AH, Seke Etet PF, Kipanyula MJ, Vecchio L, Tagne Simo R, Njamnshi AK, Lukong KE, Mimche PN. Insulin-like growth factor-1 signaling in the tumor microenvironment: Carcinogenesis, cancer drug resistance, and therapeutic potential. Front Endocrinol (Lausanne) 2022; 13:927390. [PMID: 36017326 PMCID: PMC9395641 DOI: 10.3389/fendo.2022.927390] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 07/15/2022] [Indexed: 11/13/2022] Open
Abstract
The tumor microenvironment fuels tumorigenesis and induces the development of resistance to anticancer drugs. A growing number of reports support that the tumor microenvironment mediates these deleterious effects partly by overexpressing insulin-like growth factor 1 (IGF-1). IGF-1 is known for its role to support cancer progression and metastasis through the promotion of neovascularization in transforming tissues, and the promotion of the proliferation, maintenance and migration of malignant cells. Anti-IGF therapies showed potent anticancer effects and the ability to suppress cancer resistance to various chemotherapy drugs in in vivo and in vitro preclinical studies. However, high toxicity and resistance to these agents are increasingly being reported in clinical trials. We review data supporting the notion that tumor microenvironment mediates tumorigenesis partly through IGF-1 signaling pathway. We also discuss the therapeutic potential of IGF-1 receptor targeting, with special emphasis on the ability of IGF-R silencing to overcome chemotherapy drug resistance, as well as the challenges for clinical use of anti-IGF-1R therapies.
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Affiliation(s)
- Armel H. Nwabo Kamdje
- Department of Physiological Sciences and Biochemistry, Faculty of Medicine and Biomedical Sciences, University of Garoua, Garoua, Cameroon
- *Correspondence: Armel H. Nwabo Kamdje,
| | - Paul F. Seke Etet
- Department of Physiological Sciences and Biochemistry, Faculty of Medicine and Biomedical Sciences, University of Garoua, Garoua, Cameroon
- Basic and Translational Research Unit, Center for Sustainable Health and Development, Garoua, Cameroon
- Neuroscience Lab, Faculty of Medicine and Biomedical Medicine, The University of Yaoundé l and Brain Research Africa Initiative (BRAIN), Yaoundé, Cameroon
| | - Maulilio J. Kipanyula
- Department of Veterinary Anatomy and Pathology, College of Veterinary Medicine and Biomedical Sciences, Sokoine University of Agriculture, Morogoro, Tanzania
| | - Lorella Vecchio
- Basic and Translational Research Unit, Center for Sustainable Health and Development, Garoua, Cameroon
| | - Richard Tagne Simo
- Department of Biomedical Sciences, Faculty of Sciences, University of Ngaoundere, Ngaoundere, Cameroon
| | - Alfred K. Njamnshi
- Neuroscience Lab, Faculty of Medicine and Biomedical Medicine, The University of Yaoundé l and Brain Research Africa Initiative (BRAIN), Yaoundé, Cameroon
| | - Kiven E. Lukong
- Department of Biochemistry, Microbiology & Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Patrice N. Mimche
- Division of Microbiology and Immunology, Department of Pathology, Molecular Medicine Program, University of Utah, Salt Lake City, UT, United States
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20
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Batoon L, McCauley LK. Cross Talk Between Macrophages and Cancer Cells in the Bone Metastatic Environment. Front Endocrinol (Lausanne) 2021; 12:763846. [PMID: 34803925 PMCID: PMC8597897 DOI: 10.3389/fendo.2021.763846] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
The skeleton is a common site for cancer metastases with the bone microenvironment providing the appropriate conditions for cancer cell colonization. Once in bone, cancer cells effectively manipulate their microenvironment to support their growth and survival. Despite previous efforts to improve treatment modalities, skeletal metastases remain with poor prognoses. This warrants an improved understanding of the mechanisms leading to bone metastasis that will aid development of effective treatments. Macrophages in the tumor microenvironment are termed tumor associated macrophages (TAMs) and their crosstalk with cancer cells is critical in regulating tumorigenicity in multiple cancers. In bone metastases, this crosstalk is also being increasingly implicated but the specific signaling pathways remain incompletely understood. Here, we summarize the reported functions, interactions, and signaling of macrophages with cancer cells during the metastatic cascade to bone. Specifically, we review and discuss how these specific interactions impact macrophages and their profiles to promote tumor development. We also discuss the potential of targeting this crosstalk to inhibit disease progression. Finally, we identify the remaining knowledge gaps that will need to be addressed in order to fully consider therapeutic targeting to improve clinical outcomes in cancer patients.
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Affiliation(s)
- Lena Batoon
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, United States
- Bones and Immunology Group, Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Laurie K. McCauley
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, United States
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21
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Chen X, Qin L, Hu W, Adah D. The mechanisms of action of Plasmodium infection against cancer. Cell Commun Signal 2021; 19:74. [PMID: 34243757 PMCID: PMC8268363 DOI: 10.1186/s12964-021-00748-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/14/2021] [Indexed: 01/12/2023] Open
Abstract
Our murine cancer model studies have demonstrated that Plasmodium infection activates the immune system that has been inhibited by cancer cells, counteracts tumor immunosuppressive microenvironment, inhibits tumor angiogenesis, inhibits tumor growth and metastasis, and prolongs the survival time of tumor-bearing mice. Based on these studies, three clinical trials of Plasmodium immunotherapy for advanced cancers have been approved and are ongoing in China. After comparing the mechanisms of action of Plasmodium immunotherapy with those of immune checkpoint blockade therapy, we propose the notion that cancer is an ecological disease and that Plasmodium immunotherapy is a systemic ecological counterattack therapy for this ecological disease, with limited side effects and without danger to public health based on the use of artesunate and other measures. Recent reports of tolerance to treatment and limitations in majority of patients associated with the use of checkpoint blockers further support this notion. We advocate further studies on the mechanisms of action of Plasmodium infection against cancer and investigations on Plasmodium-based combination therapy in the coming future.
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