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Published on: September 10, 2010
Determination of molecules regulating gene delivery using adenoviral vectors in ovarian carcinomas
A G Zeimet1, E Müller-Holzner, A Schuler
1Department of Obstetrics and Gynecology, Innsbruck University Hospital, Austria.
Abstract:
Gene therapeutic approaches currently favor adenoviral vectors over alternatively available vector systems. Ovarian cancer represents an attractive model for an intraperitoneal adenovirus-based gene therapy, which is now under intensive clinical investigation. Adenovirus-mediated gene transfer depends on adequate virus uptake and thus on the presence of sufficient amounts of high-affinity coxsackie-adenovirus receptor (CAR) and alphavbeta3- and alphavbeta5 integrins on target cells. This fact has been ignored in most ongoing clinical trials. This investigation, therefore, determined expression of CAR by immunohistochemistry in 37 ovarian carcinomas and compared it with that of alphavbeta3 and alphavbeta5 integrins. In all samples, except one undifferentiated carcinoma, CAR was immunohistochemically demonstrable. Grade 1 tumors exhibited stronger CAR immunostaining as compared with higher-grade cancers (P < 0.03). Integrins alphavbeta3 and alphavbeta5 were detectable in 62% and 65% of carcinomas, respectively, and staining for both classes correlated positively (P < 0.005). Cancers classified as undifferentiated completely lacked alphavbeta3 expression. Furthermore, in undifferentiated and grade 3 carcinomas the three molecules studied exhibited marked distributional heterogeneity with regard to focal positivity and negativity within the same tumor. Either the absence of CAR, alphavbeta3 and alphavbeta5 or the pronounced heterogeneity in their expression might seriously compromise the efficiency of adenovirus-based gene therapy in ovarian cancer.
Insights
Adenoviral gene therapy for ovarian cancer may be limited by low expression of coxsackie-adenovirus receptor (CAR) and integrins. Tumor cell heterogeneity in receptor expression further complicates efficient adenovirus-mediated gene transfer.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Adenoviral vectors are favored for gene therapy, particularly for ovarian cancer via intraperitoneal delivery.
- Adenovirus-mediated gene transfer efficacy relies on coxsackie-adenovirus receptor (CAR) and integrin expression (alphavbeta3, alphavbeta5) on target cells.
- Expression levels and distribution of these receptors in ovarian cancer are critical but often overlooked factors in clinical trials.
Purpose of the Study:
- To investigate the expression patterns of CAR, alphavbeta3, and alphavbeta5 integrins in ovarian carcinomas.
- To assess the correlation between receptor expression and tumor grade and differentiation.
- To evaluate the potential impact of receptor expression heterogeneity on adenovirus-based gene therapy efficacy in ovarian cancer.
Main Methods:
- Immunohistochemistry was employed to detect CAR, alphavbeta3, and alphavbeta5 integrin expression in 37 ovarian carcinoma samples.
- Ovarian cancer samples were analyzed for receptor expression and compared with tumor grade (Grade 1 vs. higher grades) and differentiation status (undifferentiated vs. differentiated).
Main Results:
- CAR was detectable in most ovarian carcinomas, with stronger expression observed in Grade 1 tumors compared to higher grades (P < 0.03).
- Integrins alphavbeta3 and alphavbeta5 were present in 62% and 65% of tumors, respectively, with positive correlation between their expression (P < 0.005).
- Undifferentiated carcinomas lacked alphavbeta3 expression, and undifferentiated and Grade 3 tumors showed significant heterogeneity in the expression of all three molecules.
Conclusions:
- The variable and potentially absent expression of CAR and integrins, along with significant intratumoral heterogeneity, may compromise the effectiveness of adenovirus-based gene therapy for ovarian cancer.
- Understanding receptor expression profiles is crucial for optimizing patient selection and therapeutic strategies in ovarian cancer gene therapy.
- Further research is needed to address receptor heterogeneity and develop strategies to enhance adenovirus uptake in ovarian tumors.
