Blood vessels are composed of two interacting cell types. Endothelial cells form the inner lining of the vessel wall, and perivascular cells--referred to as pericytes, vascular smooth muscle cells or mural cells--envelop the surface of the vascular tube. Over the last decades, studies of blood vessels have concentrated mainly on the endothelial cell component, especially when the first angiogenic factors were discovered, while the interest in pericytes has lagged behind. Pericytes are, however, functionally significant; when vessels lose pericytes, they become hemorrhagic and hyperdilated, which leads to conditions such as edema, diabetic retinopathy, and even embryonic lethality. Recently, pericytes have gained new attention as functional and critical contributors to tumor angiogenesis and therefore as potential new targets for antiangiogenic therapies. Pericytes are complex. Their ontogeny is not completely understood, and they perform various functions throughout the body. This review article describes the current knowledge about the nature of pericytes and their functions during vessel growth, vessel maintenance, and pathological angiogenesis.
Functions of receptor tyrosine kinases implicated in angiogenesis were pharmacologically impaired in a mouse model of pancreatic islet cancer. An inhibitor targeting VEGFRs in endothelial cells (SU5416) is effective against early-stage angiogenic lesions, but not large, well-vascularized tumors. In contrast, a kinase inhibitor incorporating selectivity for PDGFRs (SU6668) is shown to block further growth of end-stage tumors, eliciting detachment of pericytes and disruption of tumor vascularity. Importantly, PDGFRs were expressed only in perivascular cells of this tumor type, suggesting that PDGFR(+) pericytes in tumors present a complimentary target to endothelial cells for efficacious antiangiogenic therapy. Therapeutic regimes combining the two kinase inhibitors (SU5416 and SU6668) were more efficacious against all stages of islet carcinogenesis than either single agent. Combination of the VEGFR inhibitor with another distinctive kinase inhibitor targeting PDGFR activity (Gleevec) was also able to regress late-stage tumors. Thus, combinatorial targeting of receptor tyrosine kinases shows promise for treating multiple stages in tumorigenesis, most notably the often-intractable late-stage solid tumor.
IntroductionNeovascularization is a common attribute of tumors, and a wealth of functional studies support the proposition that blood vessels are crucial for the formation, growth, and dissemination of cancer (1, 2). Animal models of cancer, including both traditional tumor transplants and newer genetically engineered mouse models of cancer, have helped establish the causality of angiogenesis and presented platforms for assessing antiangiogenic therapeutic strategies (3, 4). The latter have further revealed that the normally quiescent tissue vasculature is characteristically first activated by an "angiogenic switch" to produce new blood vessels during hyperproliferative premalignant phases of carcinogenesis, before solid tumors have formed (5-7). One such model, the RIP1Tag2 line of transgenic mice, has been particularly instructive about parameters of angiogenesis and the prospects for antiangiogenic therapy. By virtue of expressing the SV40 virus oncoproteins in the pancreatic islet β cells, RIP1Tag2 mice develop islet carcinomas in a multistep pathway characterized by the temporal appearance of distinctive lesional stages: hyperplastic/dysplastic islets (with quiescent vasculature); angiogenic dysplastic islets; solid tumors with well-defined margins and fibrous capsules; and invasive carcinomas (8-10). The focal nature of the approximately 400 islets in the mouse pancreas and the relative synchronicity of progressive appearance of these lesions served to reveal the angiogenic switch as a discrete step in carcinogenesis (5). Furthermore, this model has afforded the design of preclinical therapeutic trials based on the distinctive stages of tumor development (3). In an assessment of four candidate angiogenesis inhibitors, differential stage-specific efficacy was observed: three agents (the protease inhibitor BB94/batimastat, endostatin, and angiostatin) performed best in treating early stage disease, both in the prevention trial targeting angiogenic switching in dysplastic lesions and in the mid-stage intervention trial aimed at blocking the expansive growth of small, solid tumors. Another inhibitor (TNP470) was effective at reducing the mass of bulky end-stage tumors in a regression trial, but it did not perform well in the early-stage prevention trial. These differential responses to antiangiogenic drugs suggested that there might be qualitative differences in the angiogenic vasculature in early and late stages or in the This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.
The microvasculature consists of endothelial cells and their surrounding pericytes. Few studies on the regulatory mechanisms of tumour angiogenesis have focused on pericytes. Here we report the identification of tumour-derived PDGFRbeta (+) (platelet-derived growth factor receptor beta) progenitor perivascular cells (PPCs) that have the ability to differentiate into pericytes and regulate vessel stability and vascular survival in tumours. A subset of PDGFRbeta (+) PPCs is recruited from bone marrow to perivascular sites in tumours. Specific inhibition of PDGFRbeta signalling eliminates PDGFRbeta (+) PPCs and mature pericytes around tumour vessels, leading to vascular hyperdilation and endothelial cell apoptosis in pancreatic islet tumours of transgenic Rip1Tag2 mice.
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