Abstract
Intravasation, vascular dissemination and metastasis of malignant tumor cells require their passage through the vascular wall which is commonly composed of pericytes and endothelial cells. We currently decided to investigate the relative contribution of these cell types to B16F10 melanoma metastasis in mice using an experimental model of host Shb gene (Src homology 2 domain-containing protein B) inactivation. Conditional inactivation of Shb in endothelial cells using Cdh5-CreERt2 resulted in decreased tumor growth, reduced vascular leakage, increased hypoxia and no effect on pericyte coverage and lung metastasis. RNAseq of tumor endothelial cells from these mice revealed changes in cellular components such as adherens junctions and focal adhesions by gene ontology analysis that were in line with the observed effects on leakage and junction morphology. Conditional inactivation of Shb in pericytes using Pdgfrb-CreERt2 resulted in decreased pericyte coverage of small tumor vessels with lumen, increased leakage, aberrant platelet-derived growth factor receptor B (PDGFRB) signaling and a higher frequency of lung metastasis without concomitant effects on tumor growth or oxygenation. Flow cytometry failed to reveal immune cell alterations that could explain the metastatic phenotype in this genetic model of Shb deficiency. It is concluded that proper pericyte function plays a significant role in suppressing B16F10 lung metastasis.
Highlights
When the Shb gene was inactivated in pericytes, no effects on tumor growth were observed whereas lung metastasis was increased when primary tumor resection was performed at 14 days after cell injection (Figure 1A-C)
Our findings demonstrate that decreased pericyte coverage correlates with metastasis in the current experimental models of conditional Shb gene inactivation in endothelial cells (EC) or pericytes, strongly implicating a role of pericytes in this process
The role of the immune system in this process appears to be of minor importance, despite our previous finding of reduced CD8a+ cell infiltration in melanomas grown on Shb deficient mice.[20]
Summary
The Shb gene codes for Src homology-2 domain-containing protein B (SHB) which is an adapter protein downstream of several tyrosine kinase receptors such as vascular endothelial growth factor receptor-2 (VEGFR2) and PDGFRB.[17] SHB has been found to play a role in various aspects of tumor biology. These include tumor angiogenesis[18,19,20] and immune cell responses.[21] Absence of SHB influences the characteristics of myeloid and lymphoid leukemia.[22,23,24] Of relevance to tumor angiogenesis, SHB is required for VEGF-induced vascular leakage[25,26] and immune cell infiltration.[26].
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