| RRC ID |
64920
|
| 著者 |
Tanaka M, Shimamura S, Kuriyama S, Maeda D, Goto A, Aiba N.
|
| タイトル |
SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression.
|
| ジャーナル |
Cancer Res
|
| Abstract |
Tumor-associated macrophages (TAM) play complex and pivotal roles during cancer progression. A subset of metastasis-associated macrophages accumulates within metastatic sites to promote the invasion and growth of tumor cells. Src kinase-associated phosphoprotein 2 (SKAP2), a substrate of Src family kinases, is highly expressed in macrophages from various tumors, but its contribution to the tumor-promoting behavior of TAMs is unknown. Here, we report that SKAP2 regulates podosome formation in macrophages to promote tumor invasion and metastasis. SKAP2 physically interacted with Wiskott-Aldrich syndrome protein (WASP) and localized to podosomes, which were rarely observed in SKAP2-null macrophages. The invasion of peritoneal macrophages derived from SKAP2-null mice was significantly reduced compared with wild-type macrophages, but could be rescued by the restoration of functional SKAP2 containing an intact tyrosine phosphorylation site and the ability to interact with WASP. Furthermore, SKAP2-null mice inoculated with lung cancer cells exhibited markedly decreased lung metastases characterized by reduced macrophage infiltration compared with wild-type mice. Moreover, intravenously injected SKAP2-null macrophages failed to efficiently infiltrate established tumors and promote their growth. Taken together, these findings reveal a novel mechanism by which macrophages assemble the appropriate motile machinery to infiltrate tumors and promote disease progression, and implicate SKAP2 as an attractive candidate for therapeutically targeting TAMs.
|
| 巻・号 |
76(2)
|
| ページ |
358-69
|
| 公開日 |
2016-1-15
|
| DOI |
10.1158/0008-5472.CAN-15-1879
|
| PII |
0008-5472.CAN-15-1879
|
| PMID |
26577701
|
| MeSH |
Animals
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Carcinoma, Lewis Lung / metabolism
Carcinoma, Lewis Lung / pathology
Cell Line, Tumor
Disease Progression
Female
Humans
Intracellular Signaling Peptides and Proteins / metabolism*
Macrophages / metabolism
Macrophages / pathology*
Macrophages, Peritoneal / metabolism
Macrophages, Peritoneal / pathology
Melanoma, Experimental / metabolism
Melanoma, Experimental / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasm Metastasis
Podosomes / genetics
Podosomes / metabolism
Podosomes / pathology*
RAW 264.7 Cells
|
| IF |
9.727
|
| リソース情報 |
| ヒト・動物細胞 |
LLC(RCB0558) |
