Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

B7-H3 - a new metastasis-promoting protein (#88)

Vibeke Anett Ingebrigtsen 1 , Christina Tekle 1 , Marit Kveine Nygren 1 , Cathrine Pedersen 1 , Suvi K. Leivonen 1 , Kristine Kleivi Sahlberg 1 , Øystein Fodstad 1
  1. Oslo University Hospital , Oslo, Norway

B7-H3 is a cell surface protein with immunoglobulin like structure and its high expression is associated with advanced disease and/or poor prognosis in several cancer types. We have focused on its non-immunological role and found that in an experimental metastasis model in nude rodents, silencing of B7-H3 protein resulted in reduced metastatic capacity and a significant increase in the symptom-free survival of the animals. Importantly, the expression of metastasis-associated proteins like IL-8, MMP-2, TIMPs, and phospho-Stat-3 was modulated by B7-H3 in a way that may explain the observed attenuated metastatic potential of melanoma cells1. Metastasis is closely linked to treatment resistance and we have previously shown that B7-H3 silencing increased the effect of paclitaxel by interfering with the Jak2/Stat3 pathway2. We are further studying the effect of B7-H3 on resistance by performing a drug screen to evaluate the effect of 22 anti-cancer compounds. In this screen we found that API-2 and everolimus, two small molecule inhibitors known to target proteins in the PI3K/Akt/mTOR pathway, showed a significant better effect in B7-H3 silenced metastatic breast cancer cells compared to their B7-H3 expressing counterparts. A link between B7-H3 and the PI3K/Akt/mTOR pathway was also supported by Western blot analysis demonstrating reduced phosphorylation of Akt and p70S6K in B7-H3 knockdown cells. Furthermore, preliminary data indicates that CXCR4, which is known to activate the PI3K/Akt pathway, is downregulated in B7-H3 silenced metastatic melanoma cells. Also the expression of PTEN, which negatively regulates the PI3K/Akt pathway, was reduced in B7-H3 silenced cells, probably reflecting a general lower activity in this pathway upon B7-H3 knockdown.
By our efforts to map in detail the signaling molecules affected by B7-H3 we anticipate to identify novel ways to reduce metastasis formation and increase the effect of anti-cancer drugs by inhibiting B7-H3 expression.