Semaphorin 7A promotes macrophage-mediated lymphatic remodeling during postpartum mammary gland involution and in breast cancer

Alan M. Elder, Beth A.J. Tamburini, Lyndsey S. Crump, Sarah A. Black, Veronica M. Wessells, Pepper Schedin, Virginia F. Borges, Traci R. Lyons

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Postpartum mammary gland involution is a tissue remodeling event that occurs in all mammals in the absence of nursing or after weaning to return the gland to the pre-preg-nant state. The tissue microenvironment created by involution has proven to be tumor promotional. Here we report that the GPI-linked protein semaphorin 7A (SEMA7A) is expressed on mammary epithelial cells during involution and use preclinical models to demonstrate that tumors induced during involution express high levels of SEMA7A. Overexpression of SEMA7A promoted the presence of myeloid-derived podoplanin (PDPN)-expressing cells in the tumor microenvironment and during involution. SEMA7A drove the expression of PDPN in macrophages, which led to integrin- and PDPN-dependent motility and adherence to lymphatic endothelial cells to promote lymphangiogenesis. In support of this mechanism, mammary tissue from SEMA7A-knockout mice exhibited decreased myeloid-derived PDPN-expressing cells, PDPN-expressing endothelial cells, and lymphatic vessel density. Furthermore, coexpression of SEMA7A, PDPN, and macrophage marker CD68 predicted for decreased distant metastasis-free survival in a cohort of over 600 cases of breast cancer as well as in ovarian, lung, and gastric cancers. Together, our results indicate that SEMA7A may orchestrate macrophage-mediated lymphatic vessel remodeling, which in turn drives metastasis in breast cancer. Signficance: SEMA7A, which is expressed on mammary cells during glandular involution, alters macrophage biology and lymphangiogenesis to drive breast cancer metastasis.

Original languageEnglish (US)
Pages (from-to)6473-6485
Number of pages13
JournalCancer Research
Volume78
Issue number22
DOIs
StatePublished - Nov 15 2018

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Semaphorins
Human Mammary Glands
Postpartum Period
Macrophages
Breast Neoplasms
Lymphangiogenesis
Breast
Lymphatic Vessels
Neoplasm Metastasis
GPI-Linked Proteins
Endothelial Cells
Tumor Microenvironment
Myeloid Cells
Weaning
Knockout Mice
Integrins
Ovarian Neoplasms
Stomach Neoplasms
Mammals
Lung Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Semaphorin 7A promotes macrophage-mediated lymphatic remodeling during postpartum mammary gland involution and in breast cancer. / Elder, Alan M.; Tamburini, Beth A.J.; Crump, Lyndsey S.; Black, Sarah A.; Wessells, Veronica M.; Schedin, Pepper; Borges, Virginia F.; Lyons, Traci R.

In: Cancer Research, Vol. 78, No. 22, 15.11.2018, p. 6473-6485.

Research output: Contribution to journalArticle

Elder, Alan M. ; Tamburini, Beth A.J. ; Crump, Lyndsey S. ; Black, Sarah A. ; Wessells, Veronica M. ; Schedin, Pepper ; Borges, Virginia F. ; Lyons, Traci R. / Semaphorin 7A promotes macrophage-mediated lymphatic remodeling during postpartum mammary gland involution and in breast cancer. In: Cancer Research. 2018 ; Vol. 78, No. 22. pp. 6473-6485.
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