Overview
Fibrosis at the crossroad of tissue homeostasis and cancer: The wound healing/injury repair process helps maintain tissue homeostasis but can cause fibrosis if dysregulated. It is becoming increasingly evident that the microenvironment, together with the cancer cell or incipient cancer cells, can function as co-organizers for tumor development and evolution. Evidence indicates that chronic disease-linked fibrosis and cancer-associated ECM plays a pivotal role in tumor initiation, progression, and response to therapy. Although fibrosis is obvious only in some tumors (30-60%), most tumors are stiff due to changes in stroma and ECM, suggesting common tissue biological changes. Historically, dense and rigid ECM correlates with more aggressive disease across tumor types, yet anti-cancer treatment strategies targeting/disrupting ECM components have led to disappointing (and oftentimes worse) results in the clinic. This is primarily due to our limited knowledge of underlying mechanisms of how fibrosis either suppresses or promotes cancer as a physical structure, the contribution of specific cell types (e.g. tumor cells, fibroblasts, CAFs, endothelial cells, adipocytes, etc.) to “good ECM” versus “bad ECM” as well as how these shift during disease progression, leading to a reprogrammed landscape that functions as a selective gatekeeper. Recent advances from both within and outside the cancer arena have provided some clues about the role of immune cells in shaping fibrosis and identifying immune suppressive effects of the fibrotic environment. These studies suggest that the immune system plays an integrative role in maintaining tissue homeostasis or contributing to tissue pathology. Advances in the area of fibrosis set the stage for the development of an NCI workshop to explore and discuss the underlying biology of cancer fibrosis (including mechanisms related to immunology, aging, metabolism, and ECM biology) that, in turn, will help define how fibrotic conditions can lead to increased risk of cancer, how fibrosis can promote cancer progression, and how targeting fibrosis might be coupled to other approaches such as immunotherapies to enhance treatment responses.