Abstract #5666: Systemic instigation of stromal desmoplasia and indolent tumor outgrowth via activation of granulin-expressing Sca1+/cKit- bone marrow cells

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Stromal desmoplasia, the accumulation of a myofibroblast-rich reactive connective tissue, is almost always observed in malignant human adenocarcinomas, yet the manner in which tumors acquire such a stroma is poorly understood. We previously demonstrated that certain vigorously growing xenografted human carcinomas (\#8220;instigators\#8221;) stimulate the growth of otherwise-indolent carcinoma cells, metastases, and segments of human tumor specimens (\#8220;responders\#8221;) implanted at distant anatomical sites - a process we termed \#8220;systemic instigation\#8221; (S. McAllister, et al.; Cell, 2008). We showed that systemic instigation is largely the result of activation of bone marrow cells (BMCs) that subsequently contribute to the stroma of the responding tumors; however, the identity of the activated BMCs and their contribution to outgrowth of the once-indolent cells was unknown. Here, we demonstrate that Sca1+/cKit- BMCs of hosts bearing instigating tumors are activated prior to their mobilization into the circulation and are very potent in their ability to promote outgrowth of the responding tumors. Strikingly, responding tumors, which result from either the presence of a contralateral instigating tumor or admixture of Sca1+/cKit- BMCs harvested from instigator-bearing mice, form with a desmoplastic stroma. The activated Sca1+/cKit- BMCs represent approximately two percent of the total bone marrow population and are unique in their tumor-promoting ability, as Sca1+/cKit- BMCs from non-instigator-bearing and control animals do not support responding tumor outgrowth. Furthermore, gene expression profiling of the Sca1+/cKit- BMCs from instigator- and non-instigator-bearing mice identified granulin, a pluripotent secreted growth factor, as the most highly upregulated gene in the activated BMCs. We found that granulin is indeed expressed by bone marrow-derived cells that are recruited into the responding tumor stroma, and that granulin treatment enhances the growth of responding tumors in vivo. Moreover, a series of in vitro studies revealed that granulin does not directly affect the proliferation of the responder cells but, rather, induces fibroblasts to express alpha-smooth muscle actin (ACTA2), a myofibroblast marker. These myofibroblasts, in turn, enhance the growth of the responding tumor cells. Finally, by mining existing microarray datasets, we show that high granulin expression in human breast cancers is associated with shorter disease-free survival. Our results reveal that the formation of desmoplastic stroma, a condition that is associated with invasive carcinomas, can be instigated systemically by certain tumors via activation of granulin-expressing Sca1+/cKit- in the bone marrow. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5666.