The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages

Yang, Yunlong; Andersson, Patrik; Hosaka, Kayoko; Zhang, Yin; Cao, Renhai; Iwamoto, Hideki; Xiao, Yang; Nakamura, Masaki; Wang, Jian; Zhuang, Rujie; Morikawa, Hiromasa; Xue, Yuan; Braun, Harald; Beyaert, Rudi; Samani, Nilesh J.; Nakae, Susumu; Hams, Emily; Dissing, Steen; Fallon, Padraic G.; Langer, Robert; Cao, Yihai

doi:10.1038/ncomms11385

Cited by 122 publications

(102 citation statements)

References 52 publications

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“…Depletion of pericytes in tumor vessels by genetic targeting or PDGFR inhibitors facilitated tumor metastasis (46,47). On the other hand, pericytes are required for promoting tumor metastasis by interacting with tumor-associated macrophages (48) or transiting to fibroblasts (49). Consistently, our studies showed that Z-GP-DAVL-BH induced a remarkable reduction of lung metastasis in the MDA-MB-231 breast cancer orthotopic transplantation xenografts.…”

Section: Discussionsupporting

confidence: 77%

Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents

Chen

Lei

Shi

et al. 2017

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 77%

Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents

Chen

Lei

Shi

et al. 2017

Journal of Clinical Investigation

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“…This finding is in agreement with the recently published data from serous ovarian cancer where perivascular PDGFR- β was also associated with shorter survival (Corvigno et al , 2016). Experimental studies have detected pro- as well as anti-metastatic effects of the perivascular cells (Xian et al , 2006; Cooke et al , 2012; Keskin et al , 2015; Yang et al , 2016). Concerning the pro-metastatic effects, mechanisms were proposed, including IL-33-dependent recruitment by perivascular cells of pro-metastatic TAMs (Yang et al , 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, depletion of pericytes in experimental primary tumours has been shown to enhance metastatis through mechanisms possibly involving tumour hypoxia and enhanced cancer cell intravasation (Xian et al , 2006; Cooke et al , 2012; Keskin et al , 2015). Other studies have instead noted prometastatic effects of PDGFR- β -positive pericytes (Yang et al , 2016). Finally, reduced perivascular coverage has been shown to facilitate infiltration of tumours by immune-suppressive myeloid-derived suppressor cells, ultimately leading to reduced immune-surveillance and increased tumour growth (Hong et al , 2015).…”

mentioning

confidence: 99%

Perivascular PDGFR-β is an independent marker for prognosis in renal cell carcinoma

et al. 2016

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Background:Renal cell carcinoma (RCC) is a highly vascularised tumour, where anti-angiogenic treatment with multi-tyrosine-kinase-inhibitor, is used for first-line treatment of metastatic disease. Variations in vascular characteristics are likely to contribute to variations in intrinsic aggressiveness of the disease. Emerging studies are identifying perivascular status, including perivascular PDGFR-β, as a determinant of prognosis in other tumour types.Methods:This work explored the impact on prognosis of vascular characteristics in RCC through analyses of a population-based collection of tumours from surgery-alone-treated patients. The quantitative data from a panel of vascular metrics were obtained through computerised image analysis of sections double-stained for expression of the endothelial cell marker CD34 together with perivascular markers α-SMA or PDGFR-β.Results:Perivascular expression of PDGFR-β and α-SMA were positively correlated to each other, and negatively correlated to vessel density. High expression of PDGFR-β and α-SMA as well as low vessel density was significantly associated with short survival in uni- and multivariate analyses. Subgroup analyses demonstrated that the prognostic impact of the perivascular markers was particularly prominent in the T4-subgroup. A novel metric, related to PDGFR-β perivascular heterogeneity, was also associated with prognosis in uni-and multi-variate analyses. This novel metric also acted as a prognosis marker in ovarian cancer.Conclusions:The study demonstrates previously unrecognised associations between RCC survival and the absolute levels, and variability, of perivascular PDGFR-β. This marker should be further explored in other RCC cohorts. Findings also suggest mechanistic analyses and studies on the relationship between perivascular status and efficacy of multi-tyrosine-kinase-inhibitors.

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“…MDSC accumulation in tumors led to increases in tumor growth, whereas restoring the PC coverage in tumors abrogated the increased MDSC trafficking to PC-deficient tumors (96). Though, another study reported that IL-33 produced by PDGF-B-stimulated PC promoted metastasis through recruitment of tumor-associated macrophages in several human and mouse graft tumor models (100). Further extensive studies will be required to understand the crosstalk of PC with immune cells different from T cells.…”

Section: Immune Regulation By Pc In the Tumor Microenvironmentmentioning

confidence: 99%

Immune Regulation by Pericytes: Modulating Innate and Adaptive Immunity

et al. 2016

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Pericytes (PC) are mural cells that surround endothelial cells in small blood vessels. PC have traditionally been credited with structural functions, being essential for vessel maturation and stabilization. However, an accumulating body of evidence suggests that PC also display immune properties. They can respond to a series of pro-inflammatory stimuli and are able to sense different types of danger due to their expression of functional pattern-recognition receptors, contributing to the onset of innate immune responses. In this context, PC not only secrete a variety of chemokines but also overexpress adhesion molecules such as ICAM-1 and VCAM-1 involved in the control of immune cell trafficking across vessel walls. In addition to their role in innate immunity, PC are involved in adaptive immunity. It has been reported that interaction with PC anergizes T cells, which is attributed, at least in part, to the expression of PD-L1. As components of the tumor microenvironment, PC can also modulate the antitumor immune response. However, their role is complex, and further studies will be required to better understand the crosstalk of PC with immune cells in order to consider them as potential therapeutic targets. In any case, PC will be looked at with new eyes by immunologists from now on.

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The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages

Cited by 122 publications

References 52 publications

Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents

Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents

Perivascular PDGFR-β is an independent marker for prognosis in renal cell carcinoma

Immune Regulation by Pericytes: Modulating Innate and Adaptive Immunity

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