The Sex-Related Interplay between TME and Cancer: On the Critical Role of Estrogen, MicroRNAs and Autophagy

Abstract

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.

Comprehensive Analysis of Prognostic Value and Immune Infiltration of NLRC4 and CASP1 in Colorectal Cancer

“…At present, the tumor microenvironment plays an increasingly important role in tumor cell survival or death. 35 , 36 Immune cell infiltration in the tumor microenvironment significantly influences tumor growth and is thought to be a vital factor in both the clinical prognosis and immunotherapy effect of cancer patients. 37 Up to now, some immunotherapy molecules, such as PD-1 and PD-L1 have been extensively studied, 38–40 but the relationship between NLRC4, CASP1 and immunotherapy has rarely been reported.…”

Hormones and Sex-Specific Medicine in Human Physiopathology

“…Non-sex-related cancers, e.g., prostate or cervix, must obviously be considered as biologically distinct [126]. In addition, the sex-related interplay between a tumor microenvironment, including estrogen and MicroRNAs, and gender disparity in cancer has more recently been underscored [127,128].…”

Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path

“…Within the TME, tumor and non-tumor cells are kept in touch through secreted soluble molecules, typically metabolites, cytokines, chemokines, microRNA, growth factors, inflammatory mediators, and extracellular matrix remodeling enzymes, as well as through the recently emerging circulating tumor cells (CTCs), exosomes, cell-free DNA (cfDNA), and apoptotic bodies [ 76 , 77 ]. The interactions between cellular and non-cellular components of the TME, through the above mediators, activate several signaling pathways, which can act by favoring or disadvantaging tumor progression, invasion, and drug resistance, as well as contributing to cancer-associated angiogenesis [ 78 , 79 ]. Often the tumor environment is characterized by hypoxia, lack of nutrients and acidity, non-permissive conditions for non-tumor cells that drive clonal selection towards highly invasive and metastatic cell phenotypes.…”