Invited Speaker Presentation 29th Lorne Cancer Conference 2017

Pericytes as microenvironmental regulators of normal and neoplastic epithelia. (#48)

Pritinder Kaur 1
  1. Curtin University, Perth, WA, Australia

Our lab has been interested in understanding the cellular and molecular interactions between epithelial cells and their mesenchymal microenvironment during homeostasis, wound repair and cancer. Our previous work has shown that human skin regeneration is attributed to both the intrinsic properties of epidermal stem and progenitor cells, and the cellular composition of their extrinsic mesenchymal microenvironment.1 This led us to investigate stromal heterogeneity in the epithelial microenvironment resulting in the identification of a rather potent sub-population of mesenchymal stem-cell like cells i.e. CD45/FAPa/VLA‑1bright/CD146+/PDGFRb+/NG2+pericytes - previously known to have a role in regulating microvessel structural stability and permeability in both normal and neoplastic conditions. We demonstrated that pericytes had a novel angiogenesis-independent function in normal skin regeneration in 3D organotypic cultures, mediated at least in part by increased deposition of the basement membrane extracellular matrix protein LN511 pericytes.2 New data from our lab show that pericytes promote symmetric cell divisions within the proliferative compartment of the epidermis resulting in the maintenance of a more normal epithelium displaying greater polarity complete with hemi-desmosomes and basement membrane assembly in vitro, driven by proteins secreted by pericytes. Current work is focused on mapping the spatial location of pericytes with respect to epidermal stem and progenitor cells in human skin in order to understand how local variations in the microenvironment are likely to dictate epithelial renewal. Other studies in our lab show that pericytes can act as “cancer-associated fibroblasts” accelerating human ovarian tumour growth and metastatic spread when co-inoculated into mice, without affecting angiogenesis quantitatively or qualitatively.3 Moreover, non-metastatic ovarian cancer cells can be induced to metastasize when co-injected with pericytes leading us to speculate that the interaction of epithelial cancer cells with mesenchymal stem cell-like pericytes leads to a more aggressive cancer, unrelated to angiogenesis. Consistent with this hypothesis, two large patient cohorts of ovarian cancer patients (AOCS and TCGA) with a high pericyte score exhibited swift relapse in less than 9 months despite treatment.3Current work in our lab seeks to investigate the mechanisms by which pericytes affect malignant conversion of cancer cells including the role of pericyte secreted factors.

  1. Li et al., J Clin Invest 2004; 2Paquet-Fifield et al., J Clin Invest 2009; 3Sinha et al., Clin Cancer Res 2015