Galectin-3 disruption impaired tumoral angiogenesis by reducing VEGF secretion from TGF beta 1-induced macrophages

Autor(es):Mostrar menos -

Longo Machado, Camila Maria ^{[1, 2, 3]} ; Sousa Andrade, Luciana Nogueira ^{[1, 2]} ; Teixeira, Veronica Rodrigues ^{[1, 2]} ; Costa, Fabricio Falconi ^{[4, 5]} ; Melo, Camila Morais ^{[1, 2]} ; dos Santos, Sofia Nascimento ^{[1, 2]} ; Nonogaki, Suely ^[6] ; Liu, Fu-Tong ^[7] ; Bernardes, Emerson Soares ^{[1, 2]} ; Camargo, Anamaria Aranha ^[8] ; Chammas, Roger ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Dept Radiol & Oncol, Lab Oncol Expt LIM24, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Inst Canc Estado Sao Paulo, Dept Radiol & Oncol, Ctr Invest Translac Oncol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Fac Med, Dept Radiol & Oncol, Lab Invest Med Radioisotopos LIM 43, Sao Paulo - Brazil

^[4] Northwestern Univ, Feinberg Sch Med, Ann & Robert H Lurie Childrens Hosp, Canc Biol & Epigen Program, Chicago Res Ctr, Chicago, IL 60614 - USA

^[5] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60614 - USA

^[6] Adolfo Lutz Inst, Dept Patol, Sao Paulo - Brazil

^[7] Acad Sinica, Inst Biomed Sci, Taipei - Taiwan

^[8] Inst Ludwig Pesquisa Canc, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CANCER MEDICINE; v. 3, n. 2, p. 201-214, APR 2014.
• Citações Web of Science: 21

Resumo

In order to study the role of galectin-3 in tumor angiogenesis associated with tumor-associated macrophages (TAM) and tumor parenchyma, the galectin-3 expression was reconstituted in Tm1 melanoma cell line that lacks this protein. Galectin-3-expressing cells (Tm1G3) and mock-vector transfected cells (Tm1N3) were injected into wild-type (WT) and galectin-3 knockout (KO) C57Bl/6 mice. Tumors originated from Tm1G3 were larger in tumor volume with enlarged functional vessels, decreased necrotic areas, and increased vascular endothelial growth factor (VEGF) protein levels. Galectin-3-nonexpressing-cells injected into WT and KO showed increased levels of transforming growth factor beta 1 (TGF beta 1) and, in WT animals this feature was also accompanied by increased VEGFR2 expression and its phosphorylation. In KO animals, tumors derived from galectin-3-expressing cells were infiltrated by CD68(+) -cells, whereas in tumors derived from galectin-3-nonexpressing-cells, CD68(+) cells failed to infiltrate tumors and accumulated in the periphery of the tumor mass. In vitro studies showed that Tm1G3 secreted more VEGF than Tm1N3 cells. In the latter case, TGF beta 1 induced VEGF production. Basal secretion of VEGF was higher in WT-bone marrow-derived macrophages (BMDM) than in KO-BMDM. TGF beta 1 induced secretion of VEGF only in WT-BMDM. Tm1G3-induced tumors had the Arginase I mRNA increased, which upregulated alternative macrophage (M2)/TAM induction. M2 stimuli, such as interleukin-4 (IL4) and TGF beta 1, increased Arginase I protein levels and galectin-3 expression in WTBMDM, but not in cells from KO mice. Hence, we report that galectin-3 disruption in tumor stroma and parenchyma decreases angiogenesis through interfering with the responses of macrophages to the interdependent VEGF and TGF beta 1 signaling pathways. (AU)

• Processo FAPESP: 98/14247-6 - Center for Research on Cell-Based Therapy
• Beneficiário: Marco Antonio Zago
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 08/11513-0 - Avaliação do papel da galectina-3 no processo adaptativo das células tumorais frente às pressões seletivas da resposta imune inflamatória e do agente quimioterápico cisplatina
• Beneficiário: Camila Maria Longo Machado
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 04/14267-0 - Mecanismos associados ao silenciamento do gene de galectina-3 ao longo da progressão tumoral de melanoma murino
• Beneficiário: Veronica Rodrigues Teixeira
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto