Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice

Moshe Elkabets, Ann M. Gifford, Christina Scheel, Bjorn Nilsson, Ferenc Reinhardt, Mark Anthony Bray, Anne E. Carpenter, Karin Jirström, Kristina Magnusson, Benjamin L. Ebert, Fredrik Pontén, Robert A. Weinberg, Sandra S. McAllister

Research output: Contribution to journalArticlepeer-review

170 Scopus citations

Abstract

Systemic instigation is a process by which endocrine signals sent from certain tumors (instigators) stimulate BM cells (BMCs), which are mobilized into the circulation and subsequently foster the growth of otherwise indolent carcinoma cells (responders) residing at distant anatomical sites. The identity of the BMCs and their specific contribution or contributions to responder tumor growth have been elusive. Here, we have demonstrated that Sca1 +cKit- hematopoietic BMCs of mouse hosts bearing instigating tumors promote the growth of responding tumors that form with a myofibroblast-rich, desmoplastic stroma. Such stroma is almost always observed in malignant human adenocarcinomas and is an indicator of poor prognosis. We then identified granulin (GRN) as the most upregulated gene in instigating Sca1+cKit- BMCs relative to counterpart control cells. The GRN+ BMCs that were recruited to the responding tumors induced resident tissue fibroblasts to express genes that promoted malignant tumor progression; indeed, treatment with recombinant GRN alone was sufficient to promote desmoplastic responding tumor growth. Further, analysis of tumor tissues from a cohort of breast cancer patients revealed that high GRN expression correlated with the most aggressive triple-negative, basal-like tumor subtype and reduced patient survival. Our data suggest that GRN and the unique hematopoietic BMCs that produce it might serve as novel therapeutic targets.

Original languageEnglish
Pages (from-to)784-799
Number of pages16
JournalJournal of Clinical Investigation
Volume121
Issue number2
DOIs
StatePublished - 1 Feb 2011
Externally publishedYes

ASJC Scopus subject areas

  • Medicine (all)

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