The Role of Fibrosis in Tumor Progression and the Dormant to Proliferative Switch

Abstract

The extracellular matrix is known to play a pivotal role in normal breast development as well as tumorigenesis and breast cancer progression. Several lines of clinical evidence have associated the presence of fibrotic-like, activated stroma with poor therapeutic response and prognosis in breast cancer patients. Recent evidence suggests that extracellular changes are requisite for the formation of a pre-metastatic niche that provides a permissive environment for disseminated breast cancer cells to survive and proliferate. It is also thought that in the absence of favorable environmental cues at a metastatic site, disseminated tumor cells can be maintained in a dormant, metabolically active state until they encounter or modulate their surroundings into an environment that supports their proliferation. We have shown in vivo that the induction of lung fibrosis via adenoviral instillation of TGFß, which results in collagen-I accumulation, can induce the proliferation of an otherwise dormant breast cancer cell line (D2.0R). We have recapitulated this dormant-to-proliferative switch by collagen-I supplementation in a three dimensional in vitro model of dormancy, suggesting that collagen-I is a major contributor to the overtly proliferative integrin β1-dependent state of the D2.0R cells in fibrotic lungs. This work has highlighted the importance of the integrin β1 pathway and its downstream effectors as principal players in sensing microenvironmental changes by dormant breast cells and activating pro-proliferative pathways resulting in overt metastases.