A novel, angiogenesis-independent role for pericytes in ovarian cancer progression and metastasis

Abstract

Cancer-associated fibroblasts (CAFs) are a heterogeneous population of cells known for their pro-tumourigenic effect in the microenvironment of solid tumours. One of their major sources is bone marrow derived mesenchymal stem cells (BM MSCs), a population with a demonstrated ability to infiltrate the site of the tumour and engage in paracrine cross-talk with the tumour cells. However, the role of a locally resident perivascular MSC population, i.e. pericytes, has not been explored in this context. Pericytes are contractile cells located around microvessels and are known for their prominent role in maintenance and stabilisation of the blood vasculature in homeostasis, and during tumour angiogenesis. However, previous data from our laboratory has shown that pericytes have the ability to promote the growth of normal epithelial cells, independent of angiogenesis. In addition, interrogation of a gene expression dataset of 215 serous ovarian cancer patients revealed that patients carrying a pericyte-specific gene expression signature bore a significantly higher risk of relapse and a lower overall chance of survival. This indicated that pericyte activity is a strong predictor of cancer recurrence and mortality. Further, this high-risk patient group was distinct from that identified by an angiogenic signature. Therefore, this thesis work was undertaken with the hypothesis that pericytes have a direct, pro-proliferative role in promoting tumour growth and metastasis, independent of their known roles in regulating angiogenesis. In the work presented here, co-injection of exogenous human pericytes with tumour cells resulted in increased tumour growth and metastasis in a xenograft model of ovarian cancer. Importantly, this effect was not associated with a concomitant increase in the extent and distribution of blood vessels, or alterations in other crucial angiogenic processes. Further, histological analyses of the xenograft tumours revealed increased tumour invasion leading to epithelial mesenchymal transition (EMT) in the presence of pericytes. Interestingly, co-injection of pericytes led to an increased infiltration of cells expressing alpha SMA to non-blood vessel-associated sites within xenograft tumours - a notable feature in tumor tissue from patients with relatively earlier recurrence of disease. In consistence with this observation, alpha SMA expression was predictive for relapse in ovarian cancer patients. Further in silico analysis revealed that extracellular matrix (ECM) remodelling and focal adhesion were the primary pathways overexpressed in ovarian cancer patients with early recurrence of disease. Together, findings from this study led to the conclusion that the MSC-like pericytes, when dissociated from blood vessels or mislocalised at non-vascular sites, can directly engage in paracrine crosstalk with tumour cells, resulting in increased proliferation, invasion and metastasis, without affecting angiogenesis. Thus, this study is the first clinical and experimental evidence for a novel, angiogenesis-independent, CAF-like role for pericytes in the ovarian tumour microenvironment and presents the possibility of pericyte-specific genes being used at the protein level as prognostic markers for ovarian cancer progression and survival. Further studies focussing on deciphering the molecular mechanisms through which pericytes exert their pro-proliferative effects in the tumour microenvironment are required for better understanding of their biology and precise role in cancer pathogenesis.