Redefinition of tumor capsule: Rho-dependent clustering of cancer-associated fibroblasts in favor of tensional homeostasis.

Fibroblasts are the most frequent cells of the connective tissues. Having the ability to sense and respond to mechanical stimuli in addition to the biochemical ones makes them crucial for such a composite-like and tension-preserving tissue. Over the last decade, the investigation of the role of these cells in tumor progression was a hot topic of research in tumor biology. Literatures almost unanimously describe the re-education of stromal fibroblasts by tumor cells in favor of tumor progression, which resulted in the birth of a new nomenclature, the cancer-associated fibroblasts. On the other hand, some studies reported anti-tumor roles for these cells. Herein, author suggests that the previously described pro-migratory and pro-contractile contexts, which respectively results in divergent and convergent distribution of fibroblasts by changing Rho-Rac1 balance, could be applied for cancer-associated fibroblasts as well. Based on this proposed concept, stromal fibroblasts could represent different roles, either pro-tumor or anti-tumor, during the course of tumor progression. In the earlier phases, they tend to assemble along tumor-stroma interface in the form of tumor capsules in order to resist tumor growth and to maintain tensional homeostasis in stroma. But in later phases, after being chronically subjected to tumor-induced chemical and mechanical stimuli, they will gradually lose their substantial abilities to oppose tumor expansion and, in contrary, will promote tumorigenesis. In summary, this paper redefines tumor capsule from chemical and mechanical standpoints as Rho-dependent clustering of cancer-associated fibroblasts in favor of tensional homeostasis. Furthermore, it proposes that stromal fibroblasts will undergo some irreversible epigenetic changes in Rac1- and Rho-related proteins through tumor-stroma crosstalk, which irreversibly diminish their ability of capsule formation. Finally, the author discusses the possible researches helping us to assess the proposed concept and its clinical implications.