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Cancer Res. 2015 Feb 1;75(3):487-96. doi: 10.1158/0008-5472.CAN-13-3339. Epub 2014 Dec 15.

Role of chitinase 3-like-1 and semaphorin 7a in pulmonary melanoma metastasis.

Author information

1
Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island.
2
Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
3
Department of Therapeutic Radiology, Yale Cancer Center, New Haven, Connecticut.
4
Section of Medical Oncology, Department of Internal Medicine, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
5
Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island. Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut. jack_elias@brown.edu.

Abstract

The prototypic chitinase-like protein Chi3l1 is induced in cancers and portends a poor prognosis, but whether it contributes to cancer progression is unknown. To address this gap in knowledge, we investigated the production of Chi3l1 in melanoma lung metastases. We found that Chi3l1 was induced during pulmonary melanoma metastasis and that this induction was regulated by the semaphorin Sema7a, interacting in stimulatory or inhibitory ways with its β1 integrin or Plexin C1 receptors, respectively. In mouse strains with genetic deletions of Chi3l1 or Sema7a, there was a significant reduction in pulmonary metastasis. Notably, antiserum raised against Chi3l1 or Sema7a phenocopied the reduction produced by genetic deletions. Melanoma lung metastasis was also decreased in the absence of IL13Rα2, a recently identified receptor for Chi3l1, consistent with a key role for Chi3l1 in melanoma spread. We confirmed roles for Sema7a and Chi3l1 in pulmonary metastasis of EMT6 breast cancer cells. Taken together, our studies establish a novel pathway through which Sem7a and its receptors regulate Chi3l1, revealing a host axis involving IL13Rα2 that plays a critical role in generating a pulmonary microenvironment that is critical to license metastasis.

PMID:
25511377
PMCID:
PMC4321965
DOI:
10.1158/0008-5472.CAN-13-3339
[Indexed for MEDLINE]
Free PMC Article

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