Abstract

Simple SummaryAutophagy is a complex cell process that allow the cell to survive in unfavorable conditions, e.g., in the lack of nutritional elements coming from the environment. Here we focused on the role played by autophagy in the crosstalk between the microenvironment surrounding the tumor and cancer cells. This environment is in fact known as pivotal in determining the growth or the inhibition of a tumor. Cancer progression and response to therapy significantly differ between women and men and the microenvironment, in particular sex hormones and microRNAs, appears a critical factor. Four representative types of cancer, i.e., colon cancer, melanoma, lymphoma, and lung cancer showing sex/gender specificities have been described herein. We underscore that the use of a “gender tailored” approach could provide a better comprehension of the cellular and molecular mechanisms of cancer growth control contributing to the development of novel therapeutic approaches towards an increasingly personalized medicine.The interplay between cancer cells and the tumor microenvironment (TME) has a fundamental role in tumor progression and response to therapy. The plethora of components constituting the TME, such as stroma, fibroblasts, endothelial and immune cells, as well as macromolecules, e.g., hormones and cytokines, and epigenetic factors, such as microRNAs, can modulate the survival or death of cancer cells. Actually, the TME can stimulate the genetically regulated programs that the cell puts in place under stress: apoptosis or, of interest here, autophagy. However, the implication of autophagy in tumor growth appears still undefined. Autophagy mainly represents a cyto-protective mechanism that allows cell survival but, in certain circumstances, also leads to the blocking of cell cycle progression, possibly leading to cell death. Since significant sex/gender differences in the incidence, progression and response to cancer therapy have been widely described in the literature, in this review, we analyzed the roles played by key components of the TME, e.g., estrogen and microRNAs, on autophagy regulation from a sex/gender-based perspective. We focused our attention on four paradigmatic and different forms of cancers—colon cancer, melanoma, lymphoma, and lung cancer—concluding that sex-specific differences may exert a significant impact on TME/cancer interaction and, thus, tumor growth.

Highlights

  • These cells dynamically interact with the tumor cells and with the components of the extracellular matrix (ECM) to constitute the tumor microenvironment (TME), which significantly contributes to tumor progression [1]

  • They observed that fragile-site associated tumor suppressor (FATS), a novel oncogene involved in lung carcinoma (LC), was significantly downregulated in non-small cell lung cancer (NSCLC) tissues compared with adjacent normal tissues and was associated with the survival of NSCLC patients

  • In A375 and B16 melanoma cell lines, this effect was associated with up-modulation of miR-142-3p and decreased expression of its target, the Ras homolog enriched in brain (Rheb) protein, with consequent suppression of mTOR signaling activation [132]

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Summary

Tumor Microenvironment

It has long been known that a tumor mass is constituted by cancer cells and by several other cell types such as smooth muscle cells, endothelial cells, fibroblasts, lymphocytes, macrophages, and, especially in some types of cancer, adipocytes These cells dynamically interact with the tumor cells and with the components of the extracellular matrix (ECM) to constitute the tumor microenvironment (TME), which significantly contributes to tumor progression [1]. A phagocytic cannibalic behavior exerted by cancer cells could provide further nutrients to cancer cells [5,6] This metabolic coupling between stromal and tumor cells would allow the exchange of metabolites, which are suitable to tumor cells in terms of increasing their proliferation and reducing cell death.

Autophagy
Sex Differences in Cancer
Estrogen and Autophagy
Estrogen and Cancer
Colon Cancer
Melanoma
Lymphoma
Lung Carcinoma
Sex-Specific Epigenetic Control
TME–Cancer Cells Crosstalk as Possible Target for Cancer Growth Control
Findings
Conclusions

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