Vandetanib, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR) and Epidermal Growth Factor Receptor (HER1), Potentiates Anti-Tumor Effects of Combined Endocrine and Trastuzumab Treatment in Estrogen Receptor-Positive (ER+)/HER2-Overexpressing Xenografts

Autor: Robin Ward, Kent Osborne, Anderson J. Ryan, SG Hilsenbeck, Rachel Schiff, R D Soliz, Luca Malorni
Rok vydání: 2009
Předmět:
Zdroj: Cancer Research. 69:5128-5128
ISSN: 1538-7445
0008-5472
DOI: 10.1158/0008-5472.sabcs-09-5128
Popis: AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Epithelial ovarian cancer (OC) is the most common cause of mortality from gynaecologic malignancies, and molecular and cellular events linked to TNF-related apoptosis-inducing ligand (TRAIL) play a particular role in OC development. We utilized a syngeneic mouse model using transformed mouse ovarian surface epithelial (MOSE) cell lines derived from C57BL/6 mice to assess implications of TRAIL in OC. We previously demonstrated that high TRAIL expression in the tumor microenvironment is associated with prolonged survival in OC cases. In addition, more than 2/3 of OC patients show a disturbed TRAIL pathway, including an epigenetic downregulation of TRAIL functional receptor DR4, and an upregulation of the inhibitor protein FLIP. %9In the current study, we aimed to explore the role of the TRAIL pathway with respect to protecting the host from the malignancy by employing the immunocompetent OC mouse model as mentioned above. Applying gain and loss of function approaches, tumorigenic MOSE cell lines were genetically modified in terms of DR5 (the only known functional TRAIL receptor in mice) and FLIP. Then, the influence of these genetic alterations on the phenotype was determined in vitro and in vivo. In a first step, ten tumorigenic MOSE cell lines were analyzed for expression of TRAIL, DR5, FLIP, and caspase-8 on mRNA as well as protein level, and compared to normal (non-tumorigenic) MOSE cells. Next, their sensitivity to TRAIL was measured. As expected, the ten MOSE cell lines exhibited differential expression for DR5, TRAIL, and c-FLIP. Interestingly, all tumorigenic MOSE cell lines showed downregulation of DR5 when compared to normal MOSE cells. Additionally, all of the cell lines were resistant to TRAIL-induced apoptosis except one (IG10). Taken together, our observations in tumorigenic MOSE cell lines reflect our previous findings in humans that a high percentage of OC patients differentially regulate DR4, DR5, and FLIP. In a next step, we focused on the well characterized MOSE ID8 and IF5 cell lines. Genetically engineered ID8 MOSE cells were inoculated intraperitoneally into wild type C57/BL6 mice. Knockdown of DR5 by shRNA in the selected ID8 cells accelerated development of ascites when compared to parental cells. Moreover, downregulation of DR5 inhibited TRAIL-induced apoptosis, and significantly increased the rate of proliferation in vivo. Our data clearly suggest that the TRAIL pathway plays a fundamental role in tumor progression in a well accepted immunocompetent OC mouse model. This finding adds additional evidence regarding the important role of TRAIL functional receptors in the resistance mechanism of TRAIL-induced apoptosis in OC. These observations serve as basis for further exploring MOSE cells with a genetically modified TRAIL pathway in other genetic backgrounds, and furthermore, supports the preclinical basis for an effective therapeutic strategy utilizing TRAIL ligand and agonistic DR5 antibodies in OC. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5128.
Databáze: OpenAIRE
Externí odkaz: