Abstract C75: Granulin‐expressing bone marrow cells promote the outgrowth of indolent tumors

We previously demonstrated that certain vigorously growing xenografted human carcinomas (“instigators”) stimulate the growth of otherwise‐indolent carcinoma cells and metastases (“responders”) implanted at distant anatomical sites — a process we termed “systemic instigation” (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 the admixture of Sca1+/cKit− BMCs harvested from instigator‐bearing mice, form with a desmoplastic stroma. Stromal desmoplasia, the accumulation of a myofibroblast‐rich reactive connective tissue, is almost always observed in malignant human adenocarcinomas. The Sca1+/cKit− BMCs do not directly give rise to stromal myofibroblasts; instead, we found that factors secreted by these BMCs induce fibroblasts to express alpha‐smooth muscle actin (ACTA2), a myofibroblast marker. 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: i) that granulin is indeed expressed by bone marrow‐derived cells that are recruited into the responding tumor stroma; ii) that treatment of human mammary fibroblasts with granulin induces ACTA2 expression; iii) that granulin treatment is sufficient to enhance responding tumor growth in vivo . Mining of existing microarray datasets revealed that high granulin expression is correlated with the expression of ACTA2 in human breast cancers and is associated with shorter disease‐free survival of breast cancer patients. Our results indicate 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: Cancer Res 2009;69(23 Suppl):C75.