The transformation of cancer-associated fibroblasts: Current perspectives on the role of TGF-ß in CAF mediated tumor progression and therapeutic resistance.

Over the last few years, the Transforming growth factor- ß (TGF-ß) has been significantly considered as an effective and ubiquitous mediator of cell growth. The cytokine, TGF-ß is being increasingly recognized as the most potent inducer of cancer cell initiation, differentiation, migration as well as progression through both the SMAD-dependent and independent pathways. There is growing evidence that supports the role of secretory cytokine TGF-ß as a crucial mediator of tumor-stroma crosstalk. Contextually, the CAFs are the prominent component of tumor stroma that helps in tumor progression and onset of chemoresistance. The interplay between the CAFs and the tumor cells through the paracrine signals is facilitated by cytokine TGF-ß to induce the malignant progression. Here in this review, we have dissected the most recent advancements in understanding the mechanisms of TGF-ß induced CAF activation, their multiple origins, and most importantly their role in conferring chemoresistance. Considering the pivotal role of TGF-ß in tumor perogression and associated stemness, it is one the proven clinical targets We have also included the clinical trials going on, targeting the TGF-ß and CAFs crosstalk with the tumor cells. Ultimately, we have underscored some of the outstanding issues that must be deciphered with utmost importance to unravel the successful strategies of anti-cancer therapies.

Active autophagy in cancer-associated fibroblasts: Recent advances in understanding the novel mechanism of tumor progression and therapeutic response.

Autophagy is primarily a homeostatic and catabolic process that is increasingly being recognized to have a pivotal role in the initiation and maintenance of cancer cells, as well as in the emergence of therapeutic resistance. Moreover, in the tumor microenvironment (TME) autophagy plays a crucial and sometimes dichotomous role in tumor progression. Recent studies show that during the early stages of tumor initiation, autophagy suppresses tumorigenesis. However, in the advanced stage of tumorigenesis, autophagy promotes cancer progression by protecting cancer cells against stressful conditions and therapeutic assault. Specifically, in cancer-associated fibroblasts (CAFs), autophagy promotes tumorigenesis not only by providing nutrients to the cancerous cells but also by inducing epithelial to mesenchymal transition, angiogenesis, stemness, and metastatic dissemination of the cancer cells, whereas in the immune cells, autophagy induces the tumor-localized immune response. In the TME, CAFs play a crucial role in cancer cell metabolism, immunoreaction, and growth. Therefore, targeting autophagy in CAFs by several pharmacological inducers like rapamycin or the inhibitor such as chloroquine has gained importance in preclinical and clinical trials. In the present review, we summarized the basic mechanism of autophagy in CAFs along with its role in driving tumorigenic progression through several emerging as well as classical hallmarks of cancer. We also addressed various autophagy inducers as well as inhibitors of autophagy for more efficient cancer management. Eventually, we prioritized some of the outstanding issues that must be addressed with utmost priority in the future to elucidate the role of autophagy in CAFs on tumor progression and therapeutic intervention.