Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice
Open Access
- 1 February 2011
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 121 (2), 784-799
- https://doi.org/10.1172/jci43757
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.Keywords
This publication has 74 references indexed in Scilit:
- The Role of the Microenvironment in Mammary Gland Development and CancerCold Spring Harbor Perspectives in Biology, 2010
- Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-κB-Dependent MannerCancer Cell, 2010
- FcRγ Activation Regulates Inflammation-Associated Squamous CarcinogenesisCancer Cell, 2010
- Paracrine Signaling by Platelet-Derived Growth Factor-CC Promotes Tumor Growth by Recruitment of Cancer-Associated FibroblastsCancer Research, 2008
- The myofibroblast and its tumoursJournal of Clinical Pathology, 2008
- Pancreatic cancer–associated stroma productionThe American Journal of Surgery, 2007
- The impact of adjuvant therapy on contralateral breast cancer risk and the prognostic significance of contralateral breast cancer: a population based study in the NetherlandsBreast Cancer Research and Treatment, 2007
- Fibrosis and cancer: Do myofibroblasts come also from epithelial cells via EMT?Journal of Cellular Biochemistry, 2007
- Fibroblasts in cancerNature Reviews Cancer, 2006
- Tissue microarrays for high-throughput molecular profiling of tumor specimensNature Medicine, 1998