Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis

Abstract

Anti-platelet-derived growth factor (PDGF) drugs are routinely used in front-line therapy for the treatment of various cancers, but the molecular mechanism underlying their dosedependent impact on vascular remodelling remains poorly understood. Here we show that anti-PDGF drugs significantly inhibit tumour growth and metastasis in high PDGF-BB-producing tumours by preventing pericyte loss and vascular permeability, whereas they promote tumour cell dissemination and metastasis in PDGF-BB-low-producing or PDGF-BB-negative tumours by ablating pericytes from tumour vessels. We show that this opposing effect is due to PDGF-b signalling in pericytes. Persistent exposure of pericytes to PDGF-BB markedly downregulates PDGF-b and inactivation of the PDGF-b signalling decreases integrin a1b1 levels, which impairs pericyte adhesion to extracellular matrix components in blood vessels. Our data suggest that tumour PDGF-BB levels may serve as a biomarker for selection of tumour-bearing hosts for anti-PDGF therapy and unsupervised use of anti-PDGF drugs could potentially promote tumour invasion and metastasis.

Pericyte–fibroblast transition promotes tumor growth and metastasis

“…To study the role of PDGF-BB, the pluripotent member of the PDGF family, in supporting CAFs, we analyzed expression levels of PDGF-BB mRNA and protein in a dozen human tumor cell lines. We previously reported a high PDGF-BB expression level in SC-A431 squamous carcinoma tumor tissue and a low PDGF-BB expression level in NB-IMR32 neuroblastoma tumor tissue (23). We have now validated those in vivo findings with in vitro cell cultures.…”

“…Various tumors also express a high level of PDGF-BB and the impact of tumor cell-derived PDGF-BB on pericytes is controversial. In contrast to endothelial cells, tumor cell-derived PDGF-BB may potentially attract pericytes to migrate from vessels through a chemoattractant gradient mechanism (23). The fate of vessel disassociated pericyte (PC) has not been clearly investigated.…”

Maintenance of antiangiogenic and antitumor effects by orally active low-dose capecitabine for long-term cancer therapy

“…Whole-mount staining was performed using our standard protocol (43)(44)(45)(46)(47). Briefly, tissues were cut into small pieces, and thin slices were fixed in 4% PFA overnight, followed by treatment with proteinase K (20 μg/mL).…”

TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling

“…for 5 min. Cell pellets were resuspended in PBS 53 . For isolation of TAMs, single cell suspensions were prepared by above mentioned collagenase digestion method.…”

“…Mice (n ¼ 6 per group) were killed by CO 2 overdose at the end of the experimentation. For analysis of tumour tissue cells including TAMs, single cell suspensions were prepared by 0.15% collagenase I and II digestion of small pieces of tumour tissue at 37°C for 60 min, and followed by filtration with a 40-mm diameter cell filter 53 . Single cell suspensions were subjected to FACS analysis according to our previous published methods using FACSort and CellQuest software (BD Bioscience, Franklin Lakes, NJ, USA).…”