Efficient Inhibition of Intra-Peritoneal Tumor Growth and Dissemination of Human Ovarian Carcinoma Cells in Nude Mice by Anti-L1-Cell Adhesion Molecule Monoclonal Antibody Treatment

Abstract

The L1 cell adhesion molecule is implicated in the control of proliferation, migration, and invasion of several tumor cell types in vitro. Recently, L1 overexpression was found to correlate with tumor progression of ovarian carcinoma, one of the most common causes of cancer-related deaths in gynecologic malignant diseases. To evaluate L1 as a potential target for ovarian cancer therapy, we investigated the effects of anti-L1 monoclonal antibodies (chCE7 and L1-11A) on proliferation and migration of L1-positive human SKOV3ip ovarian carcinoma cells in vitro and the therapeutic efficacy of L1-11A against i.p. SKOV3ip tumor growth in nude mice. In vitro, both anti-L1 antibodies efficiently inhibited the proliferation of SKOV3ip cells as well as other L1-expressing tumor cell lines (renal carcinoma, neuroblastoma, and colon carcinoma). On two cell lines, hyper-cross-linking of L1-11A with a secondary antibody was necessary for significant inhibition of proliferation, indicating that cross-linking of L1 is required for the antiproliferative effect. L1-negative prostate carcinoma cells were not influenced by antibody treatment. Biweekly treatment of ovarian carcinoma-bearing mice with L1-11A led to a dose-dependent and significant reduction of tumor burden (up to À63.5%) and ascites formation (up to À75%). This effect was associated with reduced proliferation within the tumors. L1-directed antibody-based inhibition of peritoneal growth and dissemination of human ovarian carcinoma cells represents important proof-of-principle for the development of a new therapy against one of the leading gynecologic malignant diseases. (Cancer Res 2006; 66(2): 936-43)

The adhesion molecule L1 (CD171) promotes melanoma progression

“…These results are in accordance with a recent report on efficient inhibition of intraperitoneal tumor growth and dissemination of human ovarian carcinoma cells in nude mice by L1-11A treatment. 17 However, we were unable to produce complete suppression of invasive melanoma growth in organotypic human skin culture, while staining with secondary antibody demonstrated that the added blocking antibody was present. These findings suggest that blockade of L1 adhesion molecule alone may not be sufficient to reverse invasive melanoma growth.…”

The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells

“…Recent studies have also implicated L1 in the aggressiveness of diff erent tumor types of nonneural origin such as colon cancer ( 24 ), melanoma ( 25 ), and ovarian carcinoma ( 21,26 ). However, the functional role of L1 in normal tissues outside the nervous system has remained elusive.…”

“…S3 B). To evaluate the role of L1 in transendothelial migration, CFSE-labeled moDCs were pretreated with CE7, a monoclonal antibody that has been previously shown to neutralize L1 function ( 21 ), and then allowed to cross a monolayer of TNF-␣ -activated human umbilical vein ECs (HUVECs). The inactivation of L1 in moDCs with CE7 resulted in a dramatic reduction of the transendothelial migration as compared with moDCs treated with an irrelevant antibody ( Fig.…”

“…In this context, the design of L1-targeting strategies in vivo would benefi t both from preclinical studies where L1-neutralizing antibodies showed therapeutic effi cacy in tumor-bearing mice ( 21,39 ) and from the use of L1 antibodies for imaging purposes in cancer patients ( 40 ).…”

Basolateral junctions are sufficient to suppress epithelial invasion during Drosophila oogenesis

“…The BLJ may thus be an important target for anti-cancer therapeutics because it can be manipulated from the cell surface, and is sufficient to suppress epithelial invasion. As a precedent for this idea, antibodies to L1, a human ortholog of Nrg, suppress ovarian epithelial cancer dissemination (Arlt et al, 2006). Future work will determine the degree to which the BLJ is sufficient to suppress epithelial invasion in other tissues and organisms.…”