Expression of αV-integrins in uterine serous papillary carcinomas; implications for targeted therapy with intetumumab (CNTO 95), a fully human antagonist anti-αV-integrin antibody.

Cancers of the uterine corpus are the most common gynecological cancers, with 43,470 estimated new cases and 7950 estimated deaths for 2010 in the United States.1 Although the majority of endometrial tumors are diagnosed at early stage and are characterized by a low-grade endometrioid histology (type I tumors), their rare counterparts (i.e., type II tumors, including serous papillary, clear cell, and poorly differentiated endometrioid carcinomas) are responsible for the most relapses and deaths from uterine cancer.2,3 Uterine serous papillary carcinoma (USPC) accounts for up to 10% of endometrial cancer and is characterized by an aggressive biological behavior because of its propensity for early lymphatic and intraperitoneal spread and recurrence.4,5 Thus, development of novel, potentially effective targeted therapies against USPC metastatic pathways remains a high priority. Integrins constitute a family of proteins involved in many physiological and pathological functions, including cell functioning, embryonic implantation and development, tissue morphogenesis, angiogenesis, blood clotting, wound healing, oncogenesis, metastasis, thrombosis, and inflammation.6 As transmembrane glycoproteins, they are expressed in different combinations by all cells, including platelets, leukocytes, mesenchymal tissues, and epithelial cells.7 Integrins achieve a diversity of functions by the formation of heterodimers, always consisting of one α-subunit and one β-chain, with 24 distinct combinations known so far.8 The αV subunit can associate with many different β-subunits, whereas other α-subunits dimerize with only one kind of β-chain.8 Both chains participate in the binding of the ligand, in cell-cell or cell–extracellular matrix (ECM) protein interactions. The intracellular portion of the integrin undergoes different associations with cytoskeletal elements and phosphorylation, in association with changes in cell morphology and movement, and provides signals via secondary messengers.7 Previous research has demonstrated that integrins play a role in multiple steps in tumorigenesis, including cell spreading, invasion, and survival of several types of solid tumors, such as melanoma, breast, prostate, and oral squamous cell carcinomas.9,10 Unfortunately, however, limited information is currently available on expression of αV-integrins in endometrial carcinoma.11,12 The presence of integrins on the cell surface renders them accessible to antibody-based therapies. Intetumumab (formerly CNTO 95; Centocor, Inc, Malvern, PA) is a human monoclonal antibody (mAb) that recognizes αV-integrin with high affinity (Kd = 200 pM for purified αV-chain and Kd = 1-24 nM for αV-integrins on expressing cells13). Previous studies have shown that this antibody binds αVβ1, αVβ3, αVβ5, and αVβ6; blocks αVβ3 and αVβ5; and inhibits integrin-mediated tumor growth and angiogenesis in vitro and in vivo on different animal models (mice,13 rats,13,14 and monkeys15) and in several different types of human tumors, including melanoma,13 breast,16 and small cell lung cancers.14 Phase I clinical trials have been conducted, showing that it is well tolerated in patients with advanced solid tumors17 and in hormone-refractory prostate cancer patients when administered with docetaxel and prednisone.18 To our knowledge, no studies have specifically described the expression of αV-integrins in USPCs. In this report, in an attempt to fill this gap in knowledge, we carefully investigated the surface expression of multiple αV-containing integrins in primary USPC cell lines and evaluated for the first time the in vitro potential of intetumumab as a novel targeted agent against this biologically aggressive and chemotherapy-resistant variant of endometrial cancer.