دورية أكاديمية
Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages.
| العنوان: | Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages. |
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| المؤلفون: | Frankenberger C; Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois., Rabe D; Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois., Bainer R; Department of Human Genetics, University of Chicago, Chicago, Illinois., Sankarasharma D; Department of Biochemistry and Molecular Biology, Rutgers University, Piscataway, New Jersey., Chada K; Department of Biochemistry and Molecular Biology, Rutgers University, Piscataway, New Jersey., Krausz T; Department of Pathology, University of Chicago, Chicago, Illinois., Gilad Y; Department of Human Genetics, University of Chicago, Chicago, Illinois., Becker L; Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois. m-rosner@uchicago.edu levb@uchicago.edu., Rosner MR; Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois. m-rosner@uchicago.edu levb@uchicago.edu. |
| المصدر: | Cancer research [Cancer Res] 2015 Oct 01; Vol. 75 (19), pp. 4063-73. Date of Electronic Publication: 2015 Aug 03. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Baltimore, Md. : American Association for Cancer Research Original Publication: Chicago [etc.] |
| مواضيع طبية MeSH: | Chemotaxis*, Chemokines/*physiology , Macrophages/*immunology , Mammary Neoplasms, Experimental/*immunology , Neoplasm Metastasis/*immunology , Neoplasm Proteins/*physiology , Phosphatidylethanolamine Binding Protein/*physiology , Triple Negative Breast Neoplasms/*immunology , Tumor Microenvironment/*immunology, Animals ; Cell Line, Tumor/transplantation ; Chemokine CCL5/biosynthesis ; Chemokine CCL5/genetics ; Chemokine CCL5/physiology ; Cyclohexanes/pharmacology ; Cyclohexanes/therapeutic use ; Disease-Free Survival ; Female ; Gene Expression Profiling ; Gene Knockdown Techniques ; HMGA2 Protein/physiology ; Heterografts/immunology ; Humans ; Mammary Neoplasms, Experimental/drug therapy ; Maraviroc ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; RNA, Neoplasm/biosynthesis ; RNA, Neoplasm/genetics ; Receptors, CCR5/drug effects ; Sequence Analysis, RNA ; Triazoles/pharmacology ; Triazoles/therapeutic use ; Triple Negative Breast Neoplasms/mortality |
| مستخلص: | Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. TNBC is characterized by reduced expression of metastasis suppressors such as Raf kinase inhibitory protein (RKIP), which inhibits tumor invasiveness. Mechanisms by which metastasis suppressors alter tumor cells are well characterized; however, their ability to regulate the tumor microenvironment and the importance of such regulation to metastasis suppression are incompletely understood. Here, we use species-specific RNA sequencing to show that RKIP expression in tumors markedly reduces the number and metastatic potential of infiltrating tumor-associated macrophages (TAM). TAMs isolated from nonmetastatic RKIP(+) tumors, relative to metastatic RKIP(-) tumors, exhibit a reduced ability to drive tumor cell invasion and decreased secretion of prometastatic factors, including PRGN, and shed TNFR2. RKIP regulates TAM recruitment by blocking HMGA2, resulting in reduced expression of numerous macrophage chemotactic factors, including CCL5. CCL5 overexpression in RKIP(+) tumors restores recruitment of prometastatic TAMs and intravasation, whereas treatment with the CCL5 receptor antagonist Maraviroc reduces TAM infiltration. These results highlight the importance of RKIP as a regulator of TAM recruitment through chemokines such as CCL5. The clinical significance of these interactions is underscored by our demonstration that a signature comprised of RKIP signaling and prometastatic TAM factors strikingly separates TNBC patients based on survival outcome. Collectively, our findings identify TAMs as a previously unsuspected mechanism by which the metastasis-suppressor RKIP regulates tumor invasiveness, and further suggest that TNBC patients with decreased RKIP activity and increased TAM infiltration may respond to macrophage-based therapeutics. (©2015 American Association for Cancer Research.) |
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| معلومات مُعتمدة: | UL1 TR000430 United States TR NCATS NIH HHS; TL1 TR000432 United States TR NCATS NIH HHS; R01 CA184494 United States CA NCI NIH HHS; GM087630 United States GM NIGMS NIH HHS; CA184494 United States CA NCI NIH HHS; T32 CA009594 United States CA NCI NIH HHS; CA192780 United States CA NCI NIH HHS; R01 GM087630 United States GM NIGMS NIH HHS; F31 CA192780 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (CCL5 protein, human) 0 (CCR5 protein, mouse) 0 (Ccl5 protein, mouse) 0 (Chemokine CCL5) 0 (Chemokines) 0 (Cyclohexanes) 0 (HMGA2 Protein) 0 (Neoplasm Proteins) 0 (PEBP1 protein, human) 0 (Phosphatidylethanolamine Binding Protein) 0 (RNA, Messenger) 0 (RNA, Neoplasm) 0 (Raf kinase inhibitory protein, mouse) 0 (Receptors, CCR5) 0 (Triazoles) MD6P741W8A (Maraviroc) |
| تواريخ الأحداث: | Date Created: 20150805 Date Completed: 20160130 Latest Revision: 20201226 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC4592465 |
| DOI: | 10.1158/0008-5472.CAN-14-3394 |
| PMID: | 26238785 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-7445 |
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| DOI: | 10.1158/0008-5472.CAN-14-3394 |