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

Elkabets, Moshe; Gifford, Ann M.; Scheel, Christina; Nilsson, Bjorn; Reinhardt, Ferenc; Bray, Mark-Anthony; Carpenter, Anne E.; Jirström, Karin LU ; Magnusson, Kristina and Ebert, Benjamin L., et al. (2011) In Journal of Clinical Investigation 121(2). p.784-799
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 Scal(+)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... (More)
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 Scal(+)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 Scal(+)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. (Less)
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Journal of Clinical Investigation
volume
121
issue
2
pages
784 - 799
publisher
The Journal of Clinical Investigation
external identifiers
  • wos:000286913800039
  • scopus:79551519982
ISSN
0021-9738
DOI
10.1172/JCI43757
language
English
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yes
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5a4f52fb-632e-434d-9647-9a51cb772253 (old id 1869208)
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2011-04-04 09:26:53
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2017-10-29 03:51:45
@article{5a4f52fb-632e-434d-9647-9a51cb772253,
  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 Scal(+)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 Scal(+)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.},
  author       = {Elkabets, Moshe and Gifford, Ann M. and Scheel, Christina and Nilsson, Bjorn and Reinhardt, Ferenc and Bray, Mark-Anthony and Carpenter, Anne E. and Jirström, Karin and Magnusson, Kristina and Ebert, Benjamin L. and Ponten, Fredrik and Weinberg, Robert A. and McAllister, Sandra S.},
  issn         = {0021-9738},
  language     = {eng},
  number       = {2},
  pages        = {784--799},
  publisher    = {The Journal of Clinical Investigation},
  series       = {Journal of Clinical Investigation},
  title        = {Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice},
  url          = {http://dx.doi.org/10.1172/JCI43757},
  volume       = {121},
  year         = {2011},
}