title: TGFβ signaling in myeloid cells regulates mammary carcinoma cell invasion through fibroblast interactions.
abstract: Metastasis is the most devastating aspect of cancer, however we know very little about the mechanisms of local invasion, the earliest step of metastasis. During tumor growth CD11b+ Gr1+ cells, known also as MDSCs, have been shown to promote tumor progression by a wide spectrum of effects that suppress the anti-tumor immune response. In addition to immunosuppression, CD11b+ Gr1+ cells promote metastasis by mechanisms that are currently unknown. CD11b+ Gr1+ cells localize near fibroblasts, which remodel the ECM and leave tracks for collective cell migration of carcinoma cells. In this study we discovered that CD11b+ Gr1+ cells promote invasion of mammary carcinoma cells by increasing fibroblast migration. This effect was directed by secreted factors derived from CD11b+ Gr1+ cells. We have identified several CD11b+ Gr1+ cell secreted proteins that activate fibroblast migration, including CXCL11, CXCL15, FGF2, IGF-I, IL1Ra, Resistin, and Shh. The combination of CXCL11 and FGF2 had the strongest effect on fibroblast migration that is associated with Akt1 and ERK1/2 phosphorylation. Analysis of subsets of CD11b+ Gr1+ cells identified that CD11b+ Ly6Chigh Ly6Glow cells increase fibroblast migration more than other myeloid cell populations. Additionally, tumor-derived CD11b+ Gr1+ cells promote fibroblast migration more than splenic CD11b+ Gr1+ cells of tumor-bearing mice. While TGFβ signaling in fibroblasts does not regulate their migration toward CD11b+ Gr1+ cells, however deletion of TGFβ receptor II on CD11b+ Gr1+ cells downregulates CXCL11, Shh, IGF1 and FGF2 resulting in reduced fibroblast migration. These studies show that TGFβ signaling in CD11b+ Gr1+ cells promotes fibroblast directed carcinoma invasion and suggests that perivascular CD11b+ Ly6Chigh Ly6Glow cells may be the stimulus for localized invasion leading to metastasis.
authors: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, United States of America.
authors: Aubie K
authors: AK
authors: Shaw
authors: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, United States of America.
authors: Michael W
authors: MW
authors: Pickup
authors: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, United States of America.
authors: Anna
authors: A
authors: Chytil
authors: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, United States of America.
authors: Mary
authors: M
authors: Aakre
authors: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, United States of America.
authors: Philip
authors: P
authors: Owens
authors: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, United States of America.
authors: Harold L
authors: HL
authors: Moses
authors: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, United States of America.
authors: Sergey V
authors: SV
authors: Novitskiy
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
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