Inhibition of α4β1 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 α4β1 integrin and its ligand (vascular cell adhesion molecule) VCAM-1. Integrin α4β1 expression on tumor cells is known to confer protection from therapy in other cancers, notably multiple myeloma. We evaluated the role of α4β1 integrin in response to platinum-based therapy in a mouse model of peritoneal ovarian cancer metastasis by treatment with a humanized anti-α4β1 integrin function-blocking antibody. Methods Integrin α4β1 expression on primary human ovarian cancer cells, fallopian tube and ovarian surface epithelium and fresh tumor was assessed by flow-cytometry. The therapeutic impact of anti- α4β1 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 α4β1 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-α4β1 integrin or anti-VCAM-1 with carboplatin significantly reduced tumor burden. In vitro, the combination of carboplatin and anti-α4β1 integrin antibodies resulted in increased cell death and doubling time. Conclusions Our findings support a role for α4β1 integrin in regulating treatment response to carboplatin, implicating α4β1 integrin as a potential therapeutic target to influence platinum responsiveness in otherwise resistant disease.

Glioblastoma in natalizumab‐treated multiple sclerosis patients

“…Indeed, natalizumab inhibits binding of leukocytes to vascular endothelial cell adhesion molecule 1 (VCAM‐1) by blocking α 4 β 1 or α 4 β 7 integrin receptors on leukocytes. This may be a potential therapeutic target to influence chemotherapy responsiveness in resistant disease 17, 18, 19…”

miR‐199a‐5p regulates β1 integrin through Ets‐1 to suppress invasion in breast cancer

“…High levels of β1 integrin correlate with lower survival rates in patients with invasive breast cancer . β1 integrin‐deficient MDA‐MB‐231 cells acquired more epithelial‐like morphologies and features in human triple negative breast cancer …”

“…(24) b1 integrin-deficient MDA-MB-231 cells acquired more epithelial-like morphologies and features in human triple negative breast cancer. (25) We also performed knockdown of Ets-1 by using the siRNA. Our findings demonstrated that knockdown of Ets-1 resulted in decreased expression of Ets-1 and b1 integrin in breast cancer cells.…”

Integrins

“…Natalizumab, an antibody targeting α4β1 integrin, can overcome the protection of microenvironment to malignant B-cells from rituximabinduced apoptosis [154]. The combination of carboplatin and anti-α4β1 integrin antibodies results in increased ovarian cancer cell death and doubling time in vitro and significantly reduces tumor burden in murine models of platinum-resistant peritoneal disease [155]. Integrin α4 blockade sensitizes resistant human leukemia blasts to acute lymphoblastic leukemia (ALL) chemotherapy (vincristine, dexamethasone, and L-asparaginase) in vitro and its addition to standard ALL chemotherapy prolongs the survival of NOD/SCID recipients of human pre-B ALL cells in vivo [156].…”