TGF-ß1 induced autophagy in cancer associated fibroblasts during hypoxia contributes EMT and glycolysis via MCT4 upregulation.

The Transforming growth factor-ß1 (TGF- ß1) in the tumor microenvironment (TME) is the major cytokine that acts as a mediator of tumor-stroma crosstalk, which in fact has a dual role in either promoting or suppressing tumor development. The cancer-associated fibroblasts (CAFs) are the major cell types in the TME, and the interaction with most of the epithelial cancers is the prime reason for cancer survival. However, the molecular mechanisms, associated with the TGF- ß1 induced tumor promotion through tumor-CAF crosstalk are not well understood. In the Reverse Warburg effect, CAFs feed the adjacent cancer cells by lactate produced during the aerobic glycolysis. We hypothesized that the monocarboxylate transporter, MCT4 which is implicated in lactate efflux from the CAFs, must be overexpressed in the CAFs. Contextually, to explore the role of TGF- ß1 in the hypoxia-induced autophagy in CAFs, we treated CoCl2 and external TGF- ß1 to the human dermal fibroblasts and L929 murine fibroblasts. We demonstrated that hypoxia accelerated the TGF- ß1 signaling and subsequent transformation of normal fibroblasts to CAFs. Moreover, we elucidated that synergistic induction of autophagy by hypoxia and TGF- ß1 upregulate the aerobic glycolysis and MCT4 expression in CAFs. Furthermore, we showed a positive correlation between glucose consumption and MCT4 expression in the CAFs. Autophagy was also found to be involved in the EMT in hypoxic CAFs. Collectively, these findings reveal the unappreciated role of autophagy in TME, which enhances the CAF transformation and that promotes tumor migration and metastasis via the reverse Warburg effect.

Paracrine TGF-ß1 from breast cancer contributes to chemoresistance in cancer associated fibroblasts via upregulation of the p44/42 MAPK signaling pathway.

Conventionally, Cancer-associated fibroblasts (CAFs) are considered as an inducer of chemoresistance in cancer cells. However, the underlying mechanism by which carcinomas induce chemoresistance in CAFs through tumor-stroma cross-talk is largely unknown. Henceforth, we uncovered a network of paracrine signals between carcinoma and CAFs that drives chemoresistance in CAFs. Acquired tamoxifen and 5-Fu resistant cell lines MCF-7 and MDA-MB-468 respectively showed higher apoptotic resistance compared to the parental cell. Besides, chemoresistant breast cancer cells showed overexpression of TGF-ß1 and have the higher potential to induce CAF phenotype in the normal dermal fibroblasts in a paracrine manner through the TGF-ß1 cytokine, compared to their parental cell. Moreover, the chemoresistant cancer cells augmented the EMT markers with a reduction of E-cadherin in the CAFs. Importantly we found out that the TGF- ß1 enriched conditioned media from both of the resistant cells triggered chemoresistance in the CAFs by p44/42 MAPK signaling axis. Mechanistically, pharmacological and genetic blockade of TGF-ß1 inhibits p44/42 MAPK activation with the subsequent restoration of chemosensitivity in the CAFs. Altogether we ascertained that chemoresistant cancer cells have tremendous potential to modulate the CAFs compared to the parental counterpart. Targeting TGF-ß1 and p44/42 MAPK signaling in the future may help to abrogate the chemoresistance in the CAFs.

Cancer associated fibroblast mediated chemoresistance: A paradigm shift in understanding the mechanism of tumor progression.

One of the undeniable issues with cancer eradication is the evolution of chemoresistance in due course of treatment, and the mechanisms of chemoresistance have been the subject of extensive research for several years. The efficacy of chemotherapy is hindered by cancer epithelium, mostly in a cell-autonomous mechanism. However, recently the valid experimental evidence showed that the surrounding tumor microenvironment (TME) is equivalently responsible for the induction of chemoresistance. Of the verities of cells in the tumor microenvironment, cancer-associated fibroblasts (CAFs) are the major cellular component of TME and act as a key regulator in the acquisition of cancer chemoresistance by providing a protective niche to the cancer cells against the anti-cancer drugs. Moreover, the symbiotic relationship between the tumor and CAFs to obtain key resources such as growth factors and nutrients for optimal tumor growth and proliferation favors the chemoresistance phenotype. Here, in this review, we provide an up-to-date overview of our knowledge of the role of the CAFs in inducing chemoresistance and tumor progression. We also further delineated the emerging events leading to the CAF origins and activation of normal fibroblasts to CAFs. Along with this, we also discuss the novel area of research confined to the CAF targeted therapies of cancer. The identification of CAF-specific markers may allow unveiling new targets and avenues for blunting or reverting the detrimental pro-tumorigenic potential of CAFs in the foreseeable future.

Senescence in polyploid giant cancer cells: A road that leads to chemoresistance.

Cellular senescence has been associated with age-related diseases, wound healing, fibrosis, diabetes and cancer. Senescent cells lack the capacity to proliferate, but are known to aggravate tumorigenesis. The polyploid giant cells arise from the cancer cell population mainly due to genotoxic stress caused by chemotherapy and/or radiotherapy. They exhibit features of senescence and have been reported to secrete an array of cytokines, chemokines and growth factors. These small molecules can bind to their receptors located on the surface of neighboring cells and activate/deactivate relevant signaling pathways, thereby modulating the tumor microenvironment. Some of these signaling cascade(s) might play a role in imparting therapy resistance to the cancer cells. This review throws light on the incidence of senescence and how the senescent polyploid giant cells affect the tumor microenvironment. Their role in giving rise to chemoresistant cancer cell population as well as acquired chemoresistance in the neighboring cancer cells along with various potential and established therapeutic avenues have also been discussed.

Multi-nucleated cells use ROS to induce breast cancer chemo-resistance in vitro and in vivo.

Although there is a strong correlation between multinucleated cells (MNCs) and cancer chemo-resistance in variety of cancers, our understanding of how multinucleated cells modulate the tumor micro-environment is limited. We captured multinucleated cells from triple-negative chemo-resistant breast cancers cells in a time frame, where they do not proliferate but rather significantly regulate their micro-environment. We show that oxidatively stressed MNCs induce chemo-resistance in vitro and in vivo by secreting VEGF and MIF. These factors act through the RAS/MAPK pathway to induce chemo-resistance by upregulating anti-apoptotic proteins. In MNCs, elevated reactive oxygen species (ROS) stabilizes HIF-1α contributing to increase production of VEGF and MIF. Together the data indicate, that the ROS-HIF-1α signaling axis is very crucial in regulation of chemo-resistance by MNCs. Targeting ROS-HIF-1α in future may help to abrogate drug resistance in breast cancer.