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Blood, 18 March 2010, Vol. 115, No. 11, pp. 2122-2123. This Article Full Text (PDF) e-Letter: Submit a Response Alert me when this article is cited Alert me when e-Letters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Sica, A. PubMed PubMed Citation Articles by Sica, A. Related Collections Related Article in Blood Online Social Bookmarking                         What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES & GRANULOCYTES Comment on Loges et al, page 2264 Macrophages give Gas(6) to cancer Antonio Sica ISTITUTO CLINICO HUMANITAS In this issue of Blood, Loges and colleagues have identified a novel tumor-promoting mechanism, whereby tumors educate tumor-associated macrophages to produce high levels of the mitogen Gas6, leading to tumor growth and metastasis.1 Surprisingly, this newly identified protumoral activity of tumor-associated macrophages is restricted to the selective induction of cancer cell proliferation, without interfering with cancer cell survival, tumor-associated inflammation, and angiogenesis. Gas6 is a member of the vitamin K–dependent ligand family, homologous to the blood coagulation protein S.2 These molecules bind the family of receptor tyrosine kinases (TAMRs)—that includes Tyro-3, Axl, and Mer—and control various cellular functions, including macrophage clearance of apoptotic cells and natural killer cell differentiation.3 Gas6 may also play a role as a key factor in cell survival4 and platelet aggregation.3,5 Genetic events, including gene amplification, mutations, and altered protein expression, promote the oncogenic potential of TAMRs and have been found in various human cancers.3 TAMRs display a certain degree of promiscuity and robustness, in that TAMR ligands share affinity for the entire family of receptor. Within this scenario, Gas6 has prominent affinity for Axl, which has transforming properties.3 Contrasting evidence exists as to the prognostic significance of Gas6/Axl in cancer patients. Whereas increased Gas6/Axl interaction predicts poor prognosis in patients with glioblastoma and ovarian carcinoma,6 an improved prognosis was observed in patients with renal cell carcinoma (RCC),6 demonstrating the complexity of the system. Loges et al provide new evidence on the regulation and significance of Gas6/Axl activity in cancer. Within the tumor microenvironment, tumor-associated macrophages acquire the capacity to express high levels of Gas6, suggesting that unidentified tumor-derived factor(s) contributes to their protumoral education.7 Among the possible candidates, IL-10 and M-CSF were able to induce Gas6 up-regulation in vitro. Interestingly, these factors promote M2 polarization of macrophages7 and help shape the protumoral M2 phenotype (see figure) of tumor-associated macrophages.7,8 It remains to be determined whether Gas6 represents a prototypical M2 marker and whether expression of high Gas6 levels is a feature of other tumor-associated myeloid cells, including myeloid-derived suppressor cells.9 View larger version (45K): [in this window] [in a new window]   Tumor-derived factors (TDF), likely including IL-10 and M-CSF, educate TAM for Gas6 production to fuel cancer cell proliferation. TAMRs indicates TAM family of receptor tyrosine kinases; TAM, tumor-associated macrophages; M-CSF, macrophage colony-stimulating factor; and IL-10, interleukin-10.   Using different ectopic and orthotopic syngeneic tumor models, Loges et al demonstrate that inhibition of Gas6 does not influence accumulation of CD45+ leukocytes, tumor-associated fibroblasts, angiogenesis, and coagulation, but it is limited to the selective inhibition of cancer cell proliferation. Further, the observed reduction in metastasis formation was secondary to reduced primary tumor growth. This scenario is rather surprising, as TAMRs are largely expressed by stromal components, including endothelial cells and leukocytes.3 The complex regulation of the Gas6 actions is highlighted by reports on its functional interplay with central regulators of inflammation and cell metabolism. Whereas activation of Gas6/Mer-dependent PI3K/akt pathway was reported to influence NF-B activation,3,10 alteration of the Von Hippel–Lindau tumor suppressor gene in clear cell renal cell carcinoma patients (ccRCC), a condition promoting a pseudohypoxic response and the consequent activation of the hypoxia-inducible factor-1 (HIF-1),11 results in enhanced expression of Axl.6 As tumor-associated macrophages accumulate in the hypoxic regions of a tumor12 and activation of PI3K/Akt leads to HIF-1 activity,13 it is tempting to speculate a possible link between the hypoxia/HIF-1 and Gas6/Axl pathways. The contrasting information on the prognostic significance of Gas6/Axl in cancer, along with the multiple mechanisms involved in its regulation, suggest that the complexity of its biology is also contest- and tissue-specific. Although development of TAMRs antagonists may have therapeutic limitations, due to the possible induction of autoimmune disorders (eg, Lupus-like syndrome),3 the cancer-restricted action of Gas6, along with its inertness on stroma cells, suggests that its therapeutic inhibition may well integrate strategies targeting cancer-related inflammation. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Loges S, Schmidt T, Tjwa M, et al. Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. Blood. 2010;115(11):2264–2273.[Abstract/Free Full Text] Manfioletti G, Brancolini C, Avanzi G, Schneider C. The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol. 1993;13(8):4976–4985.[Abstract/Free Full Text] Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008;100:35–83.[CrossRef][Medline] [Order article via Infotrieve] Goruppi S, Ruaro E, Schneider C. Gas6, the ligand of Axl tyrosine kinase receptor, has mitogenic and survival activities for serum starved NIH3T3 fibroblasts. Oncogene. 1996;12(3):471–480.[Medline] [Order article via Infotrieve] Angelillo-Scherrer A, de Frutos P, Aparicio C, et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med. 2001;7(2):215–221.[CrossRef][Medline] [Order article via Infotrieve] Gustafsson A, Boström AK, Ljungberg B, Axelson H, Dahlbäck B. Gas6 and the receptor tyrosine kinase Axl in clear cell renal cell carcinoma. PLoS ONE. 2009;4(10):e7575.[CrossRef][Medline] [Order article via Infotrieve] Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–444.[CrossRef][Medline] [Order article via Infotrieve] Biswas SK, Gangi L, Paul S, et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood. 2006;107(5):2112–2122.[Abstract/Free Full Text] Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 2007;117(5):1155–1166.[CrossRef][Medline] [Order article via Infotrieve] Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol. 2009;27:693–733.[CrossRef][Medline] [Order article via Infotrieve] Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–732.[CrossRef][Medline] [Order article via Infotrieve] Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66(2):605–612.[Abstract/Free Full Text] Phillips RJ, Mestas J, Gharaee-Kermani M, et al. Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha. J Biol Chem. 2005;280(23):22473–22481.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this? Related Article in Blood Online: Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6 Sonja Loges, Thomas Schmidt, Marc Tjwa, Katie van Geyte, Dirk Lievens, Esther Lutgens, Davy Vanhoutte, Delphine Borgel, Stephane Plaisance, Marc Hoylaerts, Aernout Luttun, Mieke Dewerchin, Bart Jonckx, and Peter Carmeliet Blood 2010 115: 2264-2273. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) e-Letter: Submit a Response Alert me when this article is cited Alert me when e-Letters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Sica, A. PubMed PubMed Citation Articles by Sica, A. Related Collections Related Article in Blood Online Social Bookmarking                         What's this?

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