Human Endogenous Retrovirus K in the Crosstalk Between Cancer Cells Microenvironment and Plasticity: A New Perspective for Combination Therapy

Abnormal activation of human endogenous retroviruses (HERVs) has been associated with several diseases such as cancer, autoimmunity, and neurological disorders. In particular, in cancer HERV activity and expression have been specifically associated with tumor aggressiveness and patient outcomes. Cancer cell aggressiveness is intimately linked to the acquisition of peculiar plasticity and heterogeneity based on cell stemness features, as well as on the crosstalk between cancer cells and the microenvironment. The latter is a driving factor in the acquisition of aggressive phenotypes, associated with metastasis and resistance to conventional cancer therapies. Remarkably, in different cell types and stages of development, HERV expression is mainly regulated by epigenetic mechanisms and is subjected to a very precise temporal and spatial regulation according to the surrounding microenvironment. Focusing on our research experience with HERV-K involvement in the aggressiveness and plasticity of melanoma cells, this perspective aims to highlight the role of HERV-K in the crosstalk between cancer cells and the tumor microenvironment. The implications for a combination therapy targeted at HERVs with standard approaches are discussed

Human Endogenous Retrovirus-K affects cellular plasticity and generation of stem-like CD133+ cells in melanoma cancer cells

Background: Malignant melanoma is one of the most aggressive types of skin cancers and its exact etiology is not yet clear. Tumor cell plasticity and the putative cancer stem cell subpopulations that express stem cell markers such as CD133 have been associated with melanoma tumor initiation and progression. Likewise, human endogenous retrovirus-K (HERV-K) has been linked to aggressiveness and immune evasion of metastatic melanoma. The exact mechanism leading to abnormal HERV-K gene expression in melanoma is not yet clearly elucidated. However, environmental factors such as stress conditions seem to be involved along with mechanisms interfering with the immune system. Protein mutations are no longer considered as sole drivers of melanoma tumors, which implies studying the role of HERV-K activation in melanoma development and progression is important to understand melanomagenesis and find a possible therapeutic target. Objective of the study: To investigate the potential role of HERV-K activation in cellular plasticity and stemness features of melanoma cells upon the modification of the microenvironment conditions. Materials and methods: Four metastatic and one primary melanoma cell lines were used in this study; cell lines TVM-A12 and TVM-A12-CD133+ were established in our laboratory. Different cell culture media were used to assess the cellular modification of cells upon the modification of the microenvironment. Flow cytometry, RT-PCR analysis, RNA interference assay, sphere-forming assay and migration/invasion assays were used to assess cell phenotypic modifications, expression of HERVK, stemness and metastatic features of the cell lines, respectively. SPSS software version 17 was used for the statistical analysis and statistical significance was set at P< 0.050. Results: The peculiar plasticity features of TVM-A12 cells were indicated by their ability to show specific differentiated and non-adherent grape-like cellular aggregate phenotypes in specific differentiation and serum-free stem cell media, respectively. The grape-like cellular aggregates were also accompanied by increased activation of HERV-K expression and generation of the stem-like CD133+ subpopulations melanoma cells. Interestingly, silencing of HERV-K expression in TVM-A12 cells by RNA interference significantly abolished the generation of the stem-like CD133+ subpopulations, dysregulated the grape-like cellular aggregates phenotype and suppressed their proliferation. Correspondingly, TVM-A12-CD133+ cell line was able to show cellular plasticity upon the modification of the microenvironments and displayed a significantly higher self-renewing, migration and invasion capacity than the heterogeneous TVM-A12 cell lines. More interestingly, treatment of TVM-A12 and TVM-A12-CD133+ with the NNRTIs, nevirapine and efavirenz, inhibited the expression of HERV-K and significantly induced high levels of apoptosis in TVM-A12-CD133+ cells. Conclusion: Therefore, taking these evidences together, this study demonstrated for the first time that the plasticity of melanoma cancer cells and their potential to generate the stem-like CD133+ cells under stress conditions are dependent upon HERV-K expression. Hence, given the relevance of the putative CD133+ cancer stem cells in melanoma progression we suggest HERV-K expression as a potential target of melanoma therapy in order to enhance the anti-metastatic effects and improve patient survival

Perceptions and attitudes of local people towards participatory natural resources management in the Jemma Watershed, North Shewa Zone, Ethiopia

ABSTRACTTo restore the degraded watersheds, the government of Ethiopia has recently introduced and adopted participatory natural resources management (PNRM) in different regions of the country. This study aimed at investigating the effects of the various independent variables derived from demographic, socio-economic, biophysical, institutional, and cognitive factors on the perceptions and the attitudes of local people towards the PNRM introduced in the Jemma Watershed, North Shewa Zone, Central Ethiopia. Semi-structured questionnaire comprised of closed- and open-ended questions was developed and administered to a total of n = 420 random households in five purposely selected Kebeles of the Jemma Watershed. Descriptive statistics and multiple linear regression techniques were used to analyze and interpret the household survey data. The descriptive results revealed that majority of the respondents (92.19%) agreed that they had the responsibility to protect and manage the natural resources in the Jemma Watershed. Consequently, about 83% of the respondents had already accepted the PNRM program introduced in the study watershed. The results of the multiple linear regression models revealed that several independent variables derived from demographic, socioeconomic, institutional, and cognitive factors had significant effects on the perceptions of the local people towards ‘the concept of PNRM’ (68% variance explained), ‘the presence of PNRM practice’ (61% variance explained), and ‘the problems with the existing PNRM system’ (72% variance explained). The study further uncovered that several independent variables derived from demographic, socioeconomic, institutional, and cognitive factors significantly affected the attitudes of the local people towards ‘managing the natural resources through participatory approach’ (63% variance explained), ‘having the responsibility to protect and manage the natural resources’ (75% variance explained), and ‘accepting the concept and the practice of the PNRM’ (65% variance explained). As there are still some respondents who are yet unsure to fully accept PNRM, creating public awareness on the PNRM and integrated watershed management program and practice is crucial to alleviate the problems of deforestation and land degradation, thereby enhancing the sustainable use of the natural resources in the Jemma Watershed

HERV-K activation is strictly required to sustain CD133+ melanoma cells with stemness features

Melanoma is a heterogeneous tumor in which phenotype-switching and CD133 marker have been associated with metastasis promotion and chemotherapy resistance. CD133 positive (CD133+) subpopulation has also been suggested as putative cancer stem cell (CSC) of melanoma tumor. Human endogenous retrovirus type K (HERV-K) has been described to be aberrantly activated during melanoma progression and implicated in the etiopathogenesis of disease. Earlier, we reported that stress-induced HERV-K activation promotes cell malignant transformation and reduces the immunogenicity of melanoma cells. Herein, we investigated the correlation between HERV-K and the CD133+ melanoma cells during microenvironmental modifications

Thymosin α1 interacts with Galectin-1 modulating the β-galactosides affinity and inducing alteration in the biological activity

The study of mechanism of action of Thymosin alpha 1 (T alpha 1) and the basis of the pleiotropic effect in health and disease, is one of the main focus of our ongoing research. T alpha 1 is a thymic peptide that demonstrates a peculiar ability to restore homeostasis in different physiological and pathological conditions (i.e., infections, cancer, immunodeficiency, vaccination, and aging) acting as multitasking protein depending on the host state of inflammation or immune dysfunction. However, few are the information about mechanisms of action mediated by specific T alpha 1-target protein interaction that could explain its pleiotropic effect. We investigated the interaction of T alpha 1 with Galectin-1 (Gal-1), a protein belonging to an oligosaccharide binding protein family involved in a variety of biological and pathological processes, including immunoregulation, infections, cancer progression and aggressiveness. Using molecular and cellular methodological approaches, we demonstrated the interaction be-tween these two proteins. T alpha 1 specifically inhibited the hemagglutination activity of Gal-1, the Gal-1 dependent in vitro formation of endothelial cell tubular structures, and the migration of cancer cells in wound healing assay. Physico-chemical methods revealed the details of the molecular interaction of T alpha 1 with Gal-1. Hence, the study allowed the identification of the not known until now specific interaction between T alpha 1 and Gal-1, and unraveled a novel mechanism of action of T alpha 1 that could support understanding of its pleiotropic activity