Abnormalities in Pericytes on Blood Vessels and Endothelial Sprouts in Tumors

Abstract

Endothelial cells of tumor vessels have well-documented alterations, but it is less clear whether pericytes on these vessels are abnormal or even absent.Here we report that ␣-smooth muscle actin (␣-SMA) and desmin-immunoreactive pericytes were present on >97% of blood vessels viewed by confocal microscopy in 100-m-thick sections of three different spontaneous or implanted tumors in mice. However, the cells had multiple abnormalities. Unlike pericytes on capillaries in normal pancreatic islets, which had desmin but not ␣-SMA immunoreactivity, pericytes on capillary-size vessels in insulinomas in RIP-Tag2 transgenic mice expressed both desmin and ␣-SMA. Furthermore, pericytes in RIP-Tag2 tumors, as well as those in MCa-IV breast carcinomas and Lewis lung carcinomas, had an abnormally loose association with endothelial cells and extended cytoplasmic processes deep into the tumor tissue. ␣-SMA-positive pericytes also covered 73% of endothelial sprouts in RIP-Tag2 tumors and 92% of sprouts in the other tumors. Indeed, pericyte sleeves were significantly longer than the CD31-immunoreactive endothelial cell sprouts themselves in all three types of tumors. All three tumors also contained ␣-SMA-positive myofibroblasts that resembled pericytes but were not associated with blood vessels. We conclude that pericytes are present on most tumor vessels but have multiple abnormalities, including altered expression of marker proteins. In contrast to some previous studies, the almost ubiquitous presence of pericytes on tumor vessels found in the present study may be attributed to our use of both desmin and ␣-SMA

Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-β and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation

“…In normal angiogenic processes, interaction of these cells with ECs consequently results in stabilisation of the capillary wall (Hellstrom et al, 1999). VEGF, an EC-specific angiogenic cytokine, has been shown to induce EC proliferation and migration, increase vascular permeability, stimulate disassociation of pericytes from vascular endothelium (Morikawa et al, 2002) and act as a key survival factor for EC (Gerber et al, 1998). It has been shown that simultaneous inhibition of multiple key regulatory factors of angiogenesis (p-PDGFR-b, its ligand PDGF and VEGF) will decrease the percentage of tumour vessels with pericyte coverage, induce EC apoptosis and tumour regression (Shaheen et al, 2001).…”

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…Unlike those on corresponding normal vessels, pericytes on tumour vessels uniformly express αSMA on capillary-size vessels, are loosely associated with ECs, have cytoplasmic processes that project into the tumour parenchyma, and form a sleeve around endothelial sprouts that is longer than the sprouts themselves (Morikawa et al, 2002). Indeed, pericyte deficiency may be responsible for the abnormalities seen in tumour blood vessels and may contribute to increased tumour cell permeability into the vasculature.…”

Endothelial cell functions

“…PDGF-BB is chemoattractant for smooth muscle cells, whereas signaling by TGF-b1 and Ang1/ Tie2 stabilizes the interactions between endothelial cells and smooth muscle cells. However, tumor vessels lack protection mechanisms that normal vessels acquire during growth, for example, they may lack functional pericytes and they are not always formed by a homogenous layer of endothelial cells (Hobbs et al, 1998;Hashizume et al, 2000;Morikawa et al, 2002). Tumor vessels are thus often functionally abnormal.…”