Breast cancer (BC) is the most common cancer and the fifth leading cause of death according to World Health Organization. Surgery is the main treatment for BC. After primary cancer-mass excision, in a high percentage of the cases, some breast cancer cells (BCC) with tumorigenic potential remain dormant/quiescent. In worst scenarios, dormant-BCC lose quiescence and re-activate their tumorigenic program, what extend treatments due to cancer recurrence.
The dormancy-to-activation process and subsequent tumor progression rely on the BCC- individual specific phenotype and is strictly modulated by a concrete extracellular niche. BCC are capable to modify their tumorous microenvironment according to the tumor dynamics. The extracellular matrix (ECM) is mainly secreted by cancer associated fibroblasts (CAF) and is a major component of the tumor microenvironment. Breast fibroblasts arise from multipotent breast adipose tissue stem cells (ASC) and surrounding connective tissues. ASC as mesenchymal stem cells, are recruited to the tumorigenic areas where still, their function on tumor microenvironment is still barely understand. There is agreement on cancer cells induce ASC-to-CAF transformation, event that provide the supportive extracellular microenvironment for tumor growth and have been associated with worst cancer prognosis.
We hyphotisized that the maintenance of the ASC´s proper function into BC niche would impact negatively BC progression. Up today, no treatments against CAF have been postulated but, systemic drugs against collagen or TGFβ1. Hene, we aim to answer whether a local and specific ECM could blunt BCC and ASC communication to overriding the ASC-to-CAF differentiation and then block BCC´ dormant-to-activation transition.
Among different other ECM components, we found collagen VII (ColVII), a marker of certain cancer cells´ quiescence and understudied on breast cancer, overexpressed in dormant BCC. To study role of the extracellular ColVII we used a recombinant human Collagen-VII (rhColVII) and we assessed MCF-7 proliferation. We coated our plates with 0, 2, 5, 10 and 20ng/ml rhColVII. MCF-7 transgenic line carrying GFP flag were plated on prior coated with different rhColVII concentration and we followed the cultures for 10 days. GFP signal was significantly decrease in the cultures growing on 10 and 20 ng/ml rhColVII when were compared with MCF-7 growing in vehicle or lower doses. We confirmed our results by area occupied by GFP and Ki67 staining. Surprisingly, single cell transcriptome banks and Collagen VII breast cancer tissue staining, showed that ColVII is highly expressed by stromal cells when they were compared with cancer cells and these stromal stem cells loss ColVII expression along with markers of stromal stem cells as PDGFR-alpha when are exposed to BCC secretome.
Our preliminary results suggest that ColVII is expressed mainly by cells with stromal origin in the breast tissue. ColVII is overexpressed on quiescent breast cancer cells and may be used therapeutically to override tumor grown by stromal breast tissue stem cells.