Abstract #5557: B7-H3: - a novel marker of tumor aggressiveness and chemoresistance
Authors: Christina Tekle, Vivi Ann Flørenes, Ivana Maric, Gunhild Mælandsmo, Jahn Nesland, Øystein Fodstad
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

B7-H3 has been known as an immunoregulatory protein with both stimulatory and inhibitory effects on the activation of T-cells. However, the finding that the protein is expressed in cell lines and tissue samples from a wide range of tumor types indicated that it is a tumor associated antigen. With our focus on malignant melanoma, we have studied the biological function of B7-H3 in melanoma cell lines and its expression in tissue samples from melanoma patients. We have recently reported that the B7-H3 protein has a potential role in the metastatic process based on our preclinical findings that knock down of B7-H3 in melanoma cells resulted in a significant inhibition of cell migration and invasion, and in parallel the expression of IL-8 and MMP-9 was significantly reduced. As IL-8 expression induces MMP-9 expression which is involved in extracellular matrix degradation, this suggests that B7-H3 might play a role in metastasis through interaction with IL-8 and MMP-9. Previously, correlations have been reported between high B7-H3 expression and lymph node metastasis and tumor infiltration in patients with non-small-cell lung cancer and gastric cancer, but the effects were ascribed to the putative immunoregulatory function of B7-H3. We have evaluated by IHC the expression in tissue samples from patients with different stages of malignant melanoma as well in benign nevi. Notably, strong membrane as well cystoplasmic staining was seen in the melanomas, with variation in intensity and intratumoral distribution. In benign nevi, the staining was more faint and with areas lacking expression. The results will be correlated to clinical data on progression. Furthermore, as malignant melanoma is known as an extremely chemoresistant tumor type, we examined the effect of dacarbazine (first line treatment of malignant melanoma) in melanoma cell lines with reduced B7-H3. Our results show that compared to non-transfected cells different melanoma cell lines were more sensitive to dacarbazine when the expression of B7-H3 was reduced by the use of siRNA. Mechanistic studies aiming at elucidating the molecular events implicated in the increased sensitivity have so far indicated that the activating transcription factor 2 (ATF-2) is involved. ATF-2 is known to be up-regulated in late stage melanoma where it is associated with chemoresistance, and in accordance with this we see a decreased phosphorylation of ATF-2 in the B7-H3 knock down cells. Furthermore, we observe that the expression level of Fas/FasL, the primary death-signaling cascade in late-stage melanoma and which reduced expression is involved in the development of chemoresistance, was restored in B7-H3 knock down cells. The alterations in ATF-2 and the Fas/FasL system make the cells more susceptible to apoptosis, and may hence explain the increased sensitivity. It is concluded that B7-H3 may prove to be a novel marker of tumor progression and chemosensitivity, and a possible target for new therapeutic strategy.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5557.