The perivascular niche regulates breast tumour dormancy

Abstract

In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumor cells (DTCs) are kept dormant, and what ‘wakes them up’, are fundamental problems in tumor biology. To address these questions, we utilized metastasis assays in mice to show that dormant DTCs reside upon microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumor-promoting, endothelial tip cell-derived factors. Our work reveals that stable microvasculature constitutes a ‘dormant niche,’ whereas sprouting neovasculature sparks micrometastatic outgrowth.

Emergent properties of neural repair: elemental biology to therapeutic concepts

“…SOCS3 is a tumor suppressor, and its function is lost in liver, lung, and squamous head and neck cancer 98. Molecular receptor systems, such as transforming growth factor β (TGFβ) receptors, induce a growth state and axonal sprouting in stroke13 and also are key molecules in metastatic transformation in cancer, such as the epithelial–mesenchymal transition 97, 99, 100. Recently described microRNAs that induce neural repair or axonal growth responses, such as miR‐9 and miR‐133,101, 102 are also closely linked to oncogenesis 103, 104, 105.…”

“…Following a stroke, progenitor cells are induced into a growth program that involves cell division, migration to a tropic cue, and association with angiogenic vessels 6, 7, 8. This is a cellular response similar to tumor metastasis, in which primary tumor cells invade adjacent tissue, circulate, and localize to angiogenic vessels 97, 99. Like metastatic tumor cells,100 migrating progenitors after stroke secrete matrix metalloproteinases to digest their way to the target tissue 106.…”

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…Recent work has linked the ECM in tumors to dormancy [9], resistance to chemotherapy or radiation [10][11][12], metastasis and metastasis tropism [13] again demonstrating the importance of understanding cell-ECM interactions. It has become apparent from both in vitro and clinical work that the ECM signals to cells through both biochemical and physical means with complex interactions between ECM composition, splicing, microstructure, and biomechanics.…”

A critical role of periostin in B-cell acute lymphoblastic leukemia

“…Bissell and colleagues demonstrated that POSTN surrounding the tip cells of the neovasculature awakens the dormant disseminated breast tumor cells and augments metastatic tumor outgrowth. 11 Recently, we further showed that POSTN is a novel component of immunosuppressive premetastatic niches and is exploited by breast tumor cells to facilitate lung metastasis. 12 These studies suggest that POSTN plays critical roles in various tumor microenvironments, including the cancer stem cell niche, 6,10 the perivascular niche 11 and the premetastatic niche 12 during tumor metastasis, and may represent a novel diagnostic and therapeutic target for tumor metastasis.…”

“…11 Recently, we further showed that POSTN is a novel component of immunosuppressive premetastatic niches and is exploited by breast tumor cells to facilitate lung metastasis. 12 These studies suggest that POSTN plays critical roles in various tumor microenvironments, including the cancer stem cell niche, 6,10 the perivascular niche 11 and the premetastatic niche 12 during tumor metastasis, and may represent a novel diagnostic and therapeutic target for tumor metastasis. While the expression pattern and function of POSTN in the development and metastasis of solid tumors have been extensively investigated, not much is known about its roles in hematological malignancies.…”