A reflection on how carcinoma-associated fibroblasts were recognized as active participants of epithelial tumorigenesis

Today's view of cancer as a systemic disease was facilitated by studies accentuating the local as well as the systemic role that non-tumorigenic cells, such as carcinoma-associated fibroblasts, play in cancer onset, development, and progression. The study highlighted in this Cancer Research Landmark was instrumental for supporting the idea that cancer is a full-body disease that depends on reciprocal interactions between cancer cells and the tumor microenvironment. Fibroblasts are mesenchymal cells of the connective tissue and are responsible for maintaining tissue homeostasis. Importantly, contractile myofibroblastic activation and immunoregulatory fibroblastic nemosis (the process of mesenchymal cell activation, followed by death, associated with release of proinflammatory molecules) constitute two functional aspects of fibroblasts that are essential for organogenesis as well as for modulating wound healing. Yet, in epithelial cancers, fibroblastic cell functions are chronically misregulated. The study by Olumi and colleagues published in Cancer Research in 1999 exemplifies how normal fibroblasts play a tumor-suppressive role and how modulating fibroblastic activity provides carcinomaassociated fibroblasts with tumor-promoting functions, similar to the needed "second hit"in a tumor suppressor gene. The emphasis on tumor/fibroblast interactions has provided a new framework for thinking about tumorigenesis as well as new targets for therapeutic intervention.