Inhibition of ?4?1 integrin increases ovarian cancer response to carboplatin.

ABSTRACT: OBJECTIVE:The inability to successfully treat women with ovarian cancer is due to the presence of metastatic disease at diagnosis and the development of platinum resistance. Ovarian cancer metastasizes throughout the peritoneal cavity by attaching to and invading through the mesothelium lining the peritoneum using a mechanism that involves ?4?1 integrin and its ligand (vascular cell adhesion molecule) VCAM-1. Integrin ?4?1 expression on tumor cells is known to confer protection from therapy in other cancers, notably multiple myeloma. We evaluated the role of ?4?1 integrin in response to platinum-based therapy in a mouse model of peritoneal ovarian cancer metastasis by treatment with a humanized anti-?4?1 integrin function-blocking antibody. METHODS:Integrin ?4?1 expression on primary human ovarian cancer cells, fallopian tube and ovarian surface epithelia and fresh tumor was assessed by flow-cytometry. The therapeutic impact of anti-?4?1 treatment was assessed in murine models of platinum-resistant peritoneal disease and in vitro using the platinum resistant ovarian cancer cell lines. RESULTS:Treatment of tumor-bearing mice with human-specific ?4?1 integrin function-blocking antibodies, anti-VCAM-1 antibody or carboplatin alone had no effect on tumor burden compared to the IgG control group. However, the combined treatment of anti-?4?1 integrin or anti-VCAM-1 with carboplatin significantly reduced tumor burden. In vitro, the combination of carboplatin and anti-?4?1 integrin antibodies resulted in increased cell death and doubling time. CONCLUSIONS:Our findings support a role for ?4?1 integrin in regulating treatment response to carboplatin, implicating ?4?1 integrin as a potential therapeutic target to influence platinum responsiveness in otherwise resistant disease.

SUBMITTER: Scalici JM 

PROVIDER: S-EPMC3939448 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature