Transforming growth factor-beta1 and myeloid-derived suppressor cells: A cancerous partnership.

Transforming growth factor-beta1 (TGF-ß1) plays a crucial role in tumor progression. It can inhibit early cancer stages but promotes tumor growth and development at the late stages of tumorigenesis. TGF-ß1 has a potent immunosuppressive function within the tumor microenvironment that largely contributes to tumor cells' immune escape and reduction in cancer immunotherapy responses. Likewise, myeloid-derived suppressor cells (MDSCs) have been postulated as leading tumor promoters and a hallmark of cancer immune evasion mechanisms. This review attempts to analyze the prominent roles of both TGF-ß1 and MDSCs and their interplay in cancer immunity. Furthermore, therapies against either TGF-ß1 or MDSCs, and their potential synergistic combination with immunotherapies are discussed. Simultaneous TGF-ß1 and MDSCs inhibition suggest a potential improvement in immunotherapy or subverted tumor immune resistance.

Gene expression profile of circulating CD34(+) cells and granulocytes in chronic myeloid leukemia.

PURPOSE: We compared the gene expression profile of peripheral blood CD34(+) cells and granulocytes in subjects with chronic myeloid leukemia (CML), with the accent on signaling pathways affected by BCR-ABL oncogene. METHODS: The microarray analyses have been performed in circulating CD34(+) cells and granulocytes from peripheral blood of 7 subjects with CML and 7 healthy donors. All studied BCR-ABL positive CML patients were in chronic phase, with a mean value of 2012±SD of CD34(+)cells/µl in peripheral blood. RESULTS: The gene expression profile was more prominent in CML CD34(+) cells (3553 genes) compared to granulocytes (2701 genes). The 41 and 39 genes were significantly upregulated in CML CD34(+) cells (HINT1, TXN, SERBP1) and granulocytes, respectively. BCR-ABL oncogene activated PI3K/AKT and MAPK signaling through significant upregulation of PTPN11, CDK4/6, and MYC and reduction of E2F1, KRAS, and NFKBIA gene expression in CD34(+) cells. Among genes linked to the inhibition of cellular proliferation by BCR-ABL inhibitor Imatinib, the FOS and STAT1 demonstrated significantly decreased expression in CML. CONCLUSION: The presence of BCR-ABL fusion gene doubled the expression quantity of genes involved in the regulation of cell cycle, proliferation and apoptosis of CD34(+) cells. These results determined the modified genes in PI3K/AKT and MAPK signaling of CML subjects.

Transforming growth factor-beta differently regulates urokinase type plasminogen activator and matrix metalloproteinase-9 expression in mouse macrophages; analysis of intracellular signal transduction.

Transforming growth factor ß (TGF-ß) modulates capacity of macrophages to produce urokinase type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP9). uPA and MMP9 actively participate in extracellular matrix reorganization and influence macrophages chemotaxis and cell migration. Although, TGF-ß regulates uPA and MMP9 macrophages expression, the underlying intracellular signal mechanisms are not well elucidated so far. Here we have investigated the implication of TGF-ß signaling in the regulation of uPA and MMP9 expression in RAW 264.7 macrophages. The expression of uPA and MMP9 was assessed by zymography, Western blotting and RT-PCR. The involvement of Smad, MAPK or NFκB signaling pathways was evaluated by using specific inhibitors. Our results indicated that TGF-ß simultaneously increased uPA and reduced MMP9 expression. The Smad3, ERK1,2, and JNK1,2 signaling pathways seem to be the main mechanisms that mediate TGF-ß-induced uPA expression. Whereas TGF-ß-reduced MMP9 expression appears to be regulated independently by JNK1,2 activation and by NFκB signaling inhibition. Thus, our results suggested that, in murine macrophages, TGF-ß differentially regulates uPA and MMP9 expressions through different intracellular signaling mechanisms. In addition, presented data may help in understanding the role of TGF-ß in macrophages proteases regulation in inflammatory diseases.

The Metabolic Features of Tumor-Associated Macrophages: Opportunities for Immunotherapy?

Besides transformed cells, the tumors are composed of various cell types that contribute to undesirable tumor progression. Tumor-associated macrophages (TAMs) are the most abundant innate immune cells in the tumor microenvironment (TME). Within the TME, TAMs exhibit high plasticity and undergo specific functional metabolic alterations according to the availability of tumor tissue oxygen and nutrients, thus further contributing to tumorigenesis and cancer progression. Here, we review the main functional TAM metabolic patterns influenced by TME, including glycolysis, amino acid, and fatty acid metabolism. Moreover, this review discusses antitumor immunotherapies that affect TAM functionality by inducing cell repolarizing and metabolic profiles towards an antitumoral phenotype. Also, new macrophage-based cell therapeutic technologies recently developed using chimeric antigen receptor bioengineering are exposed, which may overcome all solid tumor physical barriers impeding the current adoptive cell therapies and contribute to developing novel cancer immunotherapies.

Regulation of the mesenchymal stem cell fate by interleukin-17: Implications in osteogenic differentiation.

Bone regeneration is a tightly regulated process that ensures proper repair and functionality after injury. The delicate balance between bone formation and resorption is governed by cytokines and signaling molecules released during the inflammatory response. Interleukin (IL)-17A, produced in the early phase of inflammation, influences the fate of osteoprogenitors. Due to their inherent capacity to differentiate into osteoblasts, mesenchymal stem/stromal cells (MSCs) contribute to bone healing and regeneration. This review presents an overview of IL-17A signaling and the leading cellular and molecular mechanisms by which it regulates the osteogenic differentiation of MSCs. The main findings demonstrating IL-17A's influence on osteoblastogenesis are described. To this end, divergent information exists about the capacity of IL-17A to regulate MSCs' osteogenic fate, depending on the tissue context and target cell type, along with contradictory findings in the same cell types. Therefore, we summarize the data showing both the pro-osteogenic and anti-osteogenic roles of IL-17, which may help in the understanding of IL-17A function in bone repair and regeneration.

Paclitaxel inhibits transforming growth factor-ß-increased urokinase-type plasminogen activator expression through p38 MAPK and RAW 264.7 macrophage migration.

PURPOSE: Transforming growth factor-ß (TGF-ß) induces alternative macrophage activation that favors tumor progression and immunosuppression. Meanwhile, paclitaxel (PTx) induces macrophage (Mφ) polarization towards antitumor phenotype. TGF-ß also increases tumor stroma macrophage recruitment by mechanisms that include cell motility enhancement and extracellular matrix degradation. In this study, we aimed to determine whether PTx regulates macrophage migration and urokinase-type plasminogen activator (uPA) expression induced by TGF-ß. METHODS: We used mouse macrophage RAW 264.7 cells treated with PTx and TGF-ß combinations. Proliferation was analyzed by MTT and cell cycle assays. Immunofluorescence was performed to determine tubulin cytoskeleton and Smad3 nuclear localization. Western blot and transcriptional luciferase reporters were used to measure signal transduction activation. Migration was determined by wound healing assay. uPA activity was determined by zymography assay. RESULTS: PTx decreased RAW 264.7 cell proliferation by inducing G2/M cell cycle arrest and profoundly modified the tubulin cytoskeleton. Also, PTx inhibited TGF-ß-induced Smad3 activation. Furthermore, PTx decreased cell migration and uPA expression stimulated by TGF-ß. Remarkably, p38 MAPK mediated PTx inhibition of uPA activity induced by TGF-ß but it was not implicated on cell migration inhibition. CONCLUSIONS: PTx inhibits TGF-ß induction of mouse Mφ migration and uPA expression, suggesting that PTx, as TGF-ß targeting therapy, may enhance Mφ anticancer action within tumors.

Estramustine Phosphate Inhibits TGF-ß-Induced Mouse Macrophage Migration and Urokinase-Type Plasminogen Activator Production.

Transforming growth factor-beta (TGF-ß) has been demonstrated as a key regulator of immune responses including monocyte/macrophage functions. TGF-ß regulates macrophage cell migration and polarization, as well as it is shown to modulate macrophage urokinase-type plasminogen activator (uPA) production, which also contributes to macrophage chemotaxis and migration toward damaged or inflamed tissues. Microtubule (MT) cytoskeleton dynamic plays a key role during the cell motility, and any interference on the MT network profoundly affects cell migration. In this study, by using estramustine phosphate (EP), which modifies MT stability, we analysed whether tubulin cytoskeleton contributes to TGF-ß-induced macrophage cell migration and uPA expression. We found out that, in the murine macrophage cell line RAW 264.7, EP at noncytotoxic concentrations inhibited cell migration and uPA expression induced by TGF-ß. Moreover, EP greatly reduced the capacity of TGF-ß to trigger the phosphorylation and activation of its downstream Smad3 effector. Furthermore, Smad3 activation seems to be critical for the increased cell motility. Thus, our data suggest that EP, by interfering with MT dynamics, inhibits TGF-ß-induced RAW 264.7 cell migration paralleled with reduction of uPA induction, in part by disabling Smad3 activation by TGF-ß.