Il ruolo dei fibroblasti associati al cancro nel microambiente immune tumorale e nell'angiogenesi

Cancer-associated fibroblasts (CAFS) are the most common stromal cells found in tumour microenvironment (TME). They can have different origins, phenotypes and functions. As a result, researchers do not yet have exclusive markers for them. The majority of CAFs promotes cancer growth, but some subpopulations can inhibit it. The tumour immune microenvironment plays an important role in regulating the immune response and is composed of cells of the innate and adaptive immune systems. In the case of innate immune cells, particularly interesting is the crosstalk between CAFs and mast cells. In a recent study, the authors were able to integrate both stromal and cancer elements of TME using a 3D prostate cancer microtissue model. They demonstrated that mast cells can potentiate CAF-induced morphological alterations in epithelial cells by releasing a serine protease, tryptase. CAFs can also interact with T lymphocytes, promoting the transition of naive T cells into cancer-promoting cells. In the recent years, many researchers have been studying the involvement of T lymphocytes and CAFs in immune escape. One recent discovery is the characterization of antigen-presenting cancer associated fibroblasts in the tumour immune microenvironment of pancreatic ductal carcinoma. These cells can induce the transition of naive CD4+ T cells into Treg cells. Tregs are key modulators of the immune escape in cancer, so their inhibition might be a target for future clinical therapy. Moreover, CAFs can interact with immune checkpoints. They express several ligands of immune checkpoint molecules, such as PD-L1, which can inhibit T cell activation, impairing the antitumour immune response. For instance, an interesting study demonstrated that CAFs can induce cell proliferation and inhibit cell apoptosis by regulating ERK5/PDL1 signalling in colorectal cancer. It is also known that CAFs play an important role in the tumour angiogenesis, the process by which new blood vessels form from pre-existing ones. Angiogenesis is promoted by several factors, such as VEGFA. This is the most used as a target for clinical therapy. However, some patients do not benefit from these treatments since vessels can develop resistance to anti-VEGF-therapy. For this purpose, researchers are studying other factors involved in the angiogenesis. An example is the transcription factor, FOSL2, which is highly expressed in breast CAFs. The target of FOSL2 has been recently identified as Wnt5a, a glycoprotein involved in cancer growth. The authors observed that FOSL2 and Wnt5a promote tubule formation, invasion and sprouting of human umbilical vein endothelial cells. This suggests that CAFs promote VEGF-independent angiogenesis in breast cancer by the regulation of FOSL2, which transcriptionally activates Wnt5a. Therefore, FOSL2 might be a new potential target for the development of efficient VEGF-independent treatment. However, a further understanding of CAFs and their interactions with tumour microenvironment is still needed to produce new therapeutic strategies against cancer growth.