title: TGFβ modulates inflammatory cytokines and growth factors to create premetastatic microenvironment and stimulate lung metastasis.
abstract: The formation of tumor-promoting premetastatic microenvironment plays a pivotal role on metastatic progression. Understanding how the primary tumor can promote the formation of premetastatic microenvironment in the lung will aid discovery of a final cure for metastatic breast cancer. The murine 4T1 mammary carcinoma cells were injected into the mammary fat pads of the BALB/c mice. Days 0-14 were considered the premetastatic phase. Lung tissues were examined using hematoxylin-eosin staining and transmission electron microscopy. After intravenous injection of TGFβ1 pretreated 4T1 cells, the relative pulmonary vascular permeability was quantified, the extravasation, survival, and proliferation of tumor cells in premetastatic lungs were evaluated, and the levels of S100A8, S100A9, VEGF, and Angpt2 were detected in tumor-bearing mice. The results showed that during the premetastatic phase, an inflammatory response and inflammation-induced vascular hyperpermeability were established, leading to an abnormal pulmonary microenvironment, which facilitated extravasation of circulating tumor cells, and subsequent survival and proliferation of metastatic tumor cells in a TGFβ-dependent manner. Moreover, the expressions of S100A8, S100A9, VEGF, and Angpt2 were increased, and an induction of these genes by TGFβ was further observed in premetastatic lungs. Thus, this study demonstrated that TGFβ promoted the creation of premetastatic microenvironment by modulating certain crucial inflammatory cytokines and growth factors, and finally enhanced the ability of circulating cells to seed the lung.
authors.affiliation: Pharmacology Laboratory of Traditional Chinese Medicine, Longhua Hospital, 725 Wanpingnan Road, Shanghai, 200032, China.
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Ye
authors.forename: Sheng
authors.initials: S
authors.lastname: Liu
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wu
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Sun
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary* / Q000648:ultrastructure; D051379:Mice; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D040501:Calgranulin A; D040502:Calgranulin B; D016207:Cytokines; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A