Anthony M. P. Montgomery

Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels

A single intravascular injection of a cyclic peptide or monoclonal antibody antagonist of integrin alpha v beta 3 disrupts ongoing angiogenesis on the chick chorioallantoic membrane (CAM). This leads to the rapid regression of histologically distinct human tumors transplanted onto the CAM. Induction of angiogenesis by a tumor or cytokine promotes vascular cell entry into the cell cycle and expression of integrin alpha v beta 3. After angiogenesis is initiated, antagonists of this integrin induce apoptosis of the proliferative angiogenic vascular cells, leaving preexisting quiescent blood vessels unaffected. We demonstrate therefore that ligation of integrin alpha v beta 3 is required for the survival and maturation of newly forming blood vessels, an event essential for the proliferation of tumors.

Proteases and Protease Inhibitors in Tumor Progression

Our understanding of the role of matrix degrading proteases in cancer has dramatically expanded over the last two decades. From correlative observations linking proteases to cancer progression, we have accumulated evidence supporting a causal role for proteases in various steps of tumor progression and have become increasingly aware of the complex interactions that exist among proteases. Specific natural inhibitors of these proteases have also been identified and their role as potent cytostatic agents in cancer has been suggested. In this article some of the concepts on the role of proteases in cancer are discussed and examples of cooperation between matrix metalloproteinases and the plasmin/plasminogen activators system are presented. The role of protease inhibitors such as tissue inhibitor of metalloproteinases-2 (TIMP-2) and plasminogen activator inhibitor-2 (PAI-2) as inhibitors of tumor growth, invasion and metastasis is discussed.

Production and regulation of gelatinase B by human T-cells.

Here we describe for the first time the production of gelatinase B (MMP 9; 92-kDa type IV collagenase) by human peripheral blood T-lymphocytes. Expression of this enzyme was found to be dependent on the activation status of these T-cells and to be regulated by Interleukin-2.

Shedding of distinct cryptic collagen epitope (HU177) in sera of melanoma patients.

Purpose: Extracellular matrix remodeling during tumor growth plays an important role in angiogenesis. Our preclinical data suggest that a newly identified cryptic epitope (HU177) within collagen type IV regulates endothelial and melanoma cell adhesion in vitro and angiogenesis in vivo. In this study, we investigated the clinical relevance of HUI77 shedding in melanoma patient sera. Experimental Design: Serum samples from 291 melanoma patients prospectively enrolled at the New York University Medical Center and 106 control subjects were analyzed for HU177 epitope concentration by a newly developed sandwich ELISA assay. HU177 serum levels were then correlated with clinical and pathologic parameters. Results: Mean HU177 epitope concentration was 5.8 ng/mL (range, 0-139.8 ng/mL). A significant correlation was observed between HU177 concentration and nodular melanoma histologic subtype [nodular, 10.3 ± 1.6 ng/mL (mean ± SE); superficial spreading melanoma, 4.5 ± 1.1 ng/mL; all others, 6.1 ± 2.1 ng/mL; P = 0.01 by ANOVA test]. Increased HU177 shedding also correlated with tumor thickness (≤1.00 mm, 3.8 ± 1.1 ng/mL; 1.01-3.99 mm, 8.7 ± 1.3 ng/mL; ≥4.00 mm, 10.3 ± 2.4 ng/mL; P = 0.003 by ANOVA). After multivariate analysis controlling for thickness, the correlation between higher HU177 concentration and nodular subtype remained significant (P = 0.03). The mean HU177 epitope concentration in control subjects was 2.4 ng/mL. Conclusions: We report that primary melanoma can induce detectable changes in systemic levels of cryptic epitope shedding. Our data also support that nodular melanoma might be biologically distinct compared with superficial spreading type melanoma. As targeted interventions against cryptic collagen epitopes are currently undergoing phase I clinical trial testing, these findings indicate that patients with nodular melanoma may be more susceptible to such targeted therapies.

Inside-out regulation of L1 conformation, integrin binding, proteolysis, and concomitant cell migration.

The ectodomain structure and function of the neural cell adhesion molecule L1 is shown to be regulated by the intracellular phosphorylation of a novel threonine, T1172. In pancreatic cancer cells, T1172 exhibits steady-state saturated phosphorylation, an event regulated by CKII and PKC, and which further regulates cell migration.