Endothelial vascular cell adhesion molecule 1 expression is suppressed by melanoma and carcinoma.

Abstract

SummaryVascular cell adhesion molecule 1 (VCAM-1) mediates extravasation of circulating leukocytes into inflamed tissues, and presumably, plays a role in the immigration of cytotoxic effector lymphocytes into tumor metastases. Since metastases are rarely cleared by blood-borne cells from the immune system, we asked whether the tumor may escape host defense by interfering with the mechanism of effector cell extravasation. Here we show that in mice and humans, VCAM-1 expression is repressed on tumor-infiltrating vascular endothelial cells in the lungs. On lung blood vessels distant from the tumor, VCAM-1 is constitutively expressed. When melanoma and endothelioma cells were cultured on either side of a Nucleopore membrane, the expression of VCAM-1 on the endothelioma cells was inhibited and VCAM-1 gene transcription was suppressed. We propose that the downregulation of VCAM-1 is a mechanism by which vascularized melanoma and carcinoma avoid invasion by cytotoxic cells of the immune system.

DNA Vaccination Against Rat Her-2/Neu p185 More Effectively Inhibits Carcinogenesis Than Transplantable Carcinomas in Transgenic BALB/c Mice

“…The immune mechanisms elicited by ECD-TM vaccination reach hyperplastic lesions and halt their progression, but are incapable of dealing with an established carcinoma whose extracellular matrix (34,35), neovessels (36), positive pressure (37), and release of many suppressive factors (38) secure its resistance to immune attack. These factors may also account for the poor ability of ECD-TM vaccination to inhibit TUBO cell challenges.…”

Targeting TNF-α to Neoangiogenic Vessels Enhances Lymphocyte Infiltration in Tumors and Increases the Therapeutic Potential of Immunotherapy

“…These vascular abnormalities can increase the interstitial pressure, cause heterogeneous permeability, and promote irregular blood flow (2). Furthermore, angiogenic factors such as vascular endothelial cell (EC) growth factors (VEGF) and fibroblast growth factors can cause downregulation of intracellular adhesion molecule-1/2 (ICAM-1/2), VCAM-1, and CD34 on EC, a phenomenon defined as EC anergy (3). Hence, the interaction of leukocytes with the endothelial lining of vessels is reduced, and effector T cells, regardless of being induced in vivo by vaccination or adoptively transferred (4,5), may be impaired in their migration into tumor sites and cannot exert the antitumor effects necessary to eradicate the tumor (6,7).…”

The α vβ 3 integrin as a tumor homing ligand for lymphocytes

“…The homing of T cells to tumors is similarly mediated by tissue-specific adhesion molecules, although the failure of the immune system to effectively eradicate a growing tumor is testimony in part to the fact that tumor homing is inefficient. Interestingly, vascularized tumors down-regulate certain adhesion molecules, such as VCAM-1, ICAM-1, and ICAM-2, thereby preventing T lymphocytes from adhering to the vessels and subsequently migrating into the tumor [1,2,4]. In contrast, § v g 3 integrin is highly expressed by angiogenic vascular endothelium.…”

“…This is true for both constitutive recirculation of naive lymphocytes and homing of tumor-reactive lymphocytes into tumors. However, it has been demonstrated that many melanoma and carcinoma actively down-regulate the expression of cell adhesion molecules, such as vascular cell adhesion molecule (VCAM)-1 [1], ICAM-1, and ICAM-2 [2] on the endothelium adjacent to the tumor. Furthermore, endothelial cells of tumor vasculature may be unresponsive to pro-inflammatory cytokines and fail to up-regulate the expression of cell adhesion molecules [3,4].…”