Abstract 1863: The multifunconal role of B7-H3 in metastasis and drug resistance
Authors: Christina Tekle, Marit Kveine Nygren, Cathrine Pedersen, Vibeke Anett Ingebrigtsen, Kristine S Kleivi, Ming Tan, Oystein Fodstad
Journal: Cancer Research (2012)

Abstract With the advent of new targeted therapeutic alternatives some encouraging therapeutic improvements have been achieved. However, the outcome for patients with advanced metastatic disease is still dismal, and increased understanding of molecules and pathways regulating tumor growth, metastasis and resistance is needed. The overexpression of the immunoregulatory B7-H3 protein has been associated with advanced disease and poor prognosis in several types of cancer. In our own studies on clinical samples from colon cancer patients we reported for the first time a significant correlation between nuclear B7-H3 expression and poor survival. Further we have demonstrated a novel non-immunological role of B7-H3 in chemoresistance and metastasis, and have found that B7-H3 expression is associated with resistance to several chemotherapeutic compounds, including paclitaxel, docetaxel, dacarbazine, cisplatin and doxorubicin in vitro and in vivo. Mechanistic studies revealed that B7-H3 knock-down cells were sensitized to drug-induced apoptosis concurrent with abrogation of Jak2/Stat3 phosphorylation We are further studying the function of B7-H3 and its involvement in treatment response, focusing on the effect of small molecular inhibitors in B7-H3 high versus low expressing tumor cell lines applying drug screens in 384 well plates with a wide selection of such inhibitors. Preliminary results show that the mTOR inhibitor everolimus, and the AKT inhibitors API-2 and PI3K-AKT inhibitor Wortmannin have a greater effect in the B7-H3 knockdown cells compared to the vector control cells. The associations between the corresponding pathways and B7-H3 are being studied. Furthermore, we demonstrated that the B7-H3 protein regulates tumor cell migration and invasion, and experimental metastasis formation in nude mice, possibly ascribed to B7-H3 regulation of metastasis-associated molecules. We investigate the mechanistic links between the effects of B7-H3 on metastasis and resistance, e.g. by comparing drug effects on the development of metastasis in nude mice injected with B7-H3 knock-down and vector control cells and assessing the expression of relevant markers at various time points during treatment. The only phosphorylation site in the short intracellular tail of B7-H3 is a serine, and as part of elucidating the mechanisms by which B7-H3 regulates Stat3/Jak2, we are studying the effects of this serine on cell signaling by creating cell variants with mutated serine. In summary, we have demosntrated novel multifunctional, non-immunological effects of B7-H3 on clinically important cancer features and in ongoing studies we are continuing to elucidate the underlying mechanisms. Our data suggest that B7-H3 is an attractive prognostic marker and a target for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1863. doi:1538-7445.AM2012-1863