Harold L Moses

Publications of Harold L Moses

• p120-catenin is essential for terminal end bud function and mammary morphogenesis.

  Authors: Sarah J Kurley, Brian Bierie, Robert H Carnahan, Nichole A Lobdell, Michael A Davis, Ilse Hofmann, Harold L Moses, William J Muller, Albert B Reynolds

  Development (Cambridge, England). 03/2012;

  Although p120-catenin (p120) is crucial for E-cadherin function, ablation experiments in epithelial tissues from different organ systems reveal markedly different effects. Here, we examine for theAlthough p120-catenin (p120) is crucial for E-cadherin function, ablation experiments in epithelial tissues from different organ systems reveal markedly different effects. Here, we examine for the first time the consequences of p120 knockout during mouse mammary gland development. An MMTV-Cre driver was used to target knockout to the epithelium at the onset of puberty. p120 ablation was detected in approximately one-quarter of the nascent epithelium at the forth week post-partum. However, p120 null cells were essentially nonadherent, excluded from the process of terminal end bud (TEB) morphogenesis and lost altogether by week six. This elimination process caused a delay in TEB outgrowth, after which the gland developed normally from cells that had retained p120. Mechanistic studies in vitro indicate that TEB dysfunction is likely to stem from striking E-cadherin loss, failure of cell-cell adhesion and near total exclusion from the collective migration process. Our findings reveal an essential role for p120 in mammary morphogenesis.

• β-Catenin and K-RAS synergize to form primitive renal epithelial tumors with features of epithelial Wilms' tumors.

  Authors: Peter E Clark, Dina Polosukhina, Harold Love, Hernan Correa, Cheryl Coffin, Elizabeth J Perlman, Mark de Caestecker, Harold L Moses, Roy Zent

  The American journal of pathology. 12/2011; 179(6):3045-55.

  Wilms' tumor (WT) is the most common childhood renal cancer. Although mutations in known tumor-associated genes (WT1, WTX, and CATNB) occur only in a third of tumors, many tumors show evidence ofWilms' tumor (WT) is the most common childhood renal cancer. Although mutations in known tumor-associated genes (WT1, WTX, and CATNB) occur only in a third of tumors, many tumors show evidence of activated β-catenin-dependent Wnt signaling, but the molecular mechanism by which this occurs is unknown. A key obstacle to understanding the pathogenesis of WT is the paucity of mouse models that recapitulate its features in humans. Herein, we describe a transgenic mouse model of primitive renal epithelial neoplasms that have high penetrance and mimic the epithelial component of human WT. Introduction of a stabilizing β-catenin mutation restricted to the kidney is sufficient to induce primitive renal epithelial tumors; however, when compounded with activation of K-RAS, the mice develop large, bilateral, metastatic, multifocal primitive renal epithelial tumors that have the histologic and staining characteristics of the epithelial component of human WT. These highly malignant tumors have increased activation of the phosphatidylinositol 3-kinase-AKT and extracellular signal-regulated kinase pathways, increased expression of total and nuclear β-catenin, and increased downstream targets of this pathway, such as c-Myc and survivin. Thus, we developed a novel mouse model in which activated K-RAS synergizes with canonical Wnt/β-catenin signaling to form metastatic primitive renal epithelial tumors that mimic the epithelial component of human WT.

• TGF-β Receptor II Loss Promotes Mammary Carcinoma Progression by Th17 Dependent Mechanisms.

  Authors: Sergey V Novitskiy, Michael W Pickup, Agnieszka E Gorska, Philip Owens, Anna Chytil, Mary Aakre, Huiyun Wu, Yu Shyr, Harold L Moses

  Cancer discovery. 10/2011; 1(5):430-441.

  We report that IL-17 significantly increases the secretion of CXCL1 and CXCL5 from mammary carcinoma cells, which is downregulated by TGF-β through the type II TGF-β receptor (TβRII). Carcinoma cellsWe report that IL-17 significantly increases the secretion of CXCL1 and CXCL5 from mammary carcinoma cells, which is downregulated by TGF-β through the type II TGF-β receptor (TβRII). Carcinoma cells with conditional knockout of TβRII (Tgfbr2(KO)) have enhanced sensitivity to IL-17a in the stimulation of chemokine secretion. During polyoma middle T (PyMT) induced tumor progression, levels of Th17 inducing cytokines TGF-β, IL-6, IL-23 were increased in PyMT/Tgfbr2(KO) tumors, which was associated with an increased number of Th17 cells. IL-17 increased the suppressive function of MDSCs on T cells through the upregulation of Arg, IDO, and COX2. Treatment of PyMT/Tgfbr2(KO) mice with anti-IL-17 Ab decreased carcinoma growth and metastatic burden. Analysis of human breast cancer transcriptome databases showed a strong association between IL-17 gene expression and poor outcome in lymph node positive, estrogen receptor negative or luminal B subtypes suggesting potential therapeutic approaches.

• Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma.

  Authors: Hideaki Ijichi, Anna Chytil, Agnieszka E Gorska, Mary E Aakre, Brian Bierie, Motohisa Tada, Dai Mohri, Koji Miyabayashi, Yoshinari Asaoka, Shin Maeda, Tsuneo Ikenoue, Keisuke Tateishi, Christopher V E Wright, Kazuhiko Koike, Masao Omata, Harold L Moses

  The Journal of clinical investigation. 09/2011; 121(10):4106-17.

  Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized by an expanded stroma with marked fibrosis (desmoplasia). We previously generated pancreasPancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized by an expanded stroma with marked fibrosis (desmoplasia). We previously generated pancreas epithelium-specific TGF-β receptor type II (Tgfbr2) knockout mice in the context of Kras activation (mice referred to herein as Kras+Tgfbr2KO mice) and found that they developed aggressive PDAC that recapitulated the histological manifestations of the human disease. The mouse PDAC tissue showed strong expression of connective tissue growth factor (Ctgf), a profibrotic and tumor-promoting factor, especially in the tumor-stromal border area, suggesting an active tumor-stromal interaction. Here we show that the PDAC cells in Kras+Tgfbr2KO mice secreted much higher levels of several Cxc chemokines compared with mouse pancreatic intraepithelial neoplasia cells, which are preinvasive. The Cxc chemokines induced Ctgf expression in the pancreatic stromal fibroblasts, not in the PDAC cells themselves. Subcutaneous grafting studies revealed that the fibroblasts enhanced growth of PDAC cell allografts, which was attenuated by Cxcr2 inhibition. Moreover, treating the Kras+Tgfbr2KO mice with the CXCR2 inhibitor reduced tumor progression. The decreased tumor progression correlated with reduced Ctgf expression and angiogenesis and increased overall survival. Taken together, our data indicate that tumor-stromal interactions via a Cxcr2-dependent chemokine and Ctgf axis can regulate PDAC progression. Further, our results suggest that inhibiting tumor-stromal interactions might be a promising therapeutic strategy for PDAC.

• Myeloid suppressor cells regulate the lung environment--response.

  Authors: Hannah H Yan, Michael Pickup, Yanli Pang, Agnieszka E Gorska, Zhaoyang Li, Anna Chytil, Yipeng Geng, Jerome W Gray, Harold L Moses, Li Yang

  Cancer research. 07/2011; 71(14):5052-3.

• Analysis of transforming growth factor β receptor expression and signaling in higher grade meningiomas.

  Authors: Mahlon D Johnson, Aubie K Shaw, Mary J O'Connell, Fraser J Sim, Harold L Moses

  Journal of neuro-oncology. 06/2011; 103(2):277-85.

  TGF-β receptors (TGF-βRs) inhibit growth of many cell types. Loss of TGF-βRs or its signaling components have been found in several human malignancies. The expression and the role of TGF-βRs inTGF-β receptors (TGF-βRs) inhibit growth of many cell types. Loss of TGF-βRs or its signaling components have been found in several human malignancies. The expression and the role of TGF-βRs in regulating anaplastic meningioma growth has not been studied. Real time PCR found TGF-β RIII expression significantly lower in five grade III compared to eight grade I and eight grade II tumors (P = 0.0481). By western blot analysis, TGF-βRI was detected in the four fetal and adult leptomeninges, all 18 grade I, 14 grade II and six grade III meningiomas. TGF-βRII was detected in none of the leptomeninges, 55% of grade I, 71% of grade II and weak to negative in five of six the grade III meningiomas analyzed. TGF-βRIII immunoreactivity was not detected in the fetal meninges but was detected in 94% of grade I, 70% of grade II and 67% grade III tumors. Phospho-SMAD 3 and Smad 7 were detected in nearly all tumors. TGF-β1 had no effect on PDGF-BB stimulation of DNA synthesis in six of seven WHO grade II and the grade III cells. It produced an increase in phosphorylation of SMAD 3 and p38MAPK in two of four and p44/42MAPK in three of four grade II cells showing no change in DNA synthesis after treatment. Thus, only attenuated TGF-βRIII expression and TGFB growth inhibition may occur in select higher grade meningiomas. Nonetheless, restoring TGF-β inhibition of meningioma cell proliferation may be an important objective in the design of new chemotherapies for these tumors.

• Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators.

  Authors: Philip Owens, Michael W Pickup, Sergey V Novitskiy, Anna Chytil, Agnieszka E Gorska, Mary E Aakre, James West, Harold L Moses

  Proceedings of the National Academy of Sciences of the United States of America. 05/2011; 109(8):2814-9.

  Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily of signaling molecules. BMPs can elicit a wide range of effects in many cell types and have previously been shown to induceBone morphogenetic proteins (BMPs) are members of the TGF-β superfamily of signaling molecules. BMPs can elicit a wide range of effects in many cell types and have previously been shown to induce growth inhibition in carcinoma cells as well as normal epithelia. Recently, it has been demonstrated that BMP4 and BMP7 are overexpressed in human breast cancers and may have tumor suppressive and promoting effects. We sought to determine whether disruption of the BMP receptor 2 (BMPR2) would alter mammary tumor progression in mice that express the Polyoma middle T antigen. Mice expressing Polyoma middle T antigen under the mouse mammary tumor virus promoter were combined with mice that have doxycycline-inducible expression of a dominant-negative (DN) BMPR2. We did not observe any differences in tumor latency. However, mice expressing the BMPR2-DN had a fivefold increase in lung metastases. We characterized several cell autonomous changes and found that BMPR2-DN-expressing tumor cells had higher rates of proliferation. We also identified unique changes in inflammatory cells and secreted chemokines/cytokines that accompanied BMPR2-DN-expressing tumors. By immunohistochemistry, it was found that BMPR2-DN primary tumors and metastases had an altered reactive stroma, indicating specific changes in the tumor microenvironment. Among the changes we discovered were increased myeloid derived suppressor cells and the chemokine CCL9. BMP was shown to directly regulate CCL9 expression. We conclude that BMPR2 has tumor-suppressive function in mammary epithelia and microenvironment and that disruption can accelerate mammary carcinoma metastases.

• Loss of one Tgfbr2 allele in fibroblasts promotes metastasis in MMTV: polyoma middle T transgenic and transplant mouse models of mammary tumor progression.

  Authors: Wei Bin Fang, Iman Jokar, Anna Chytil, Harold L Moses, Ty Abel, Nikki Cheng

  Clinical & experimental metastasis. 03/2011; 28(4):351-66.

  Accumulation of fibroblasts is a phenomenon that significantly correlates with formation of aggressive cancers. While studies have shown that the TGF-β signaling pathway is an important regulator ofAccumulation of fibroblasts is a phenomenon that significantly correlates with formation of aggressive cancers. While studies have shown that the TGF-β signaling pathway is an important regulator of fibroblast activation, the functional contribution of TGF-β signaling in fibroblasts during multi-step tumor progression remains largely unclear. In previous studies, we used a sub-renal capsule transplantation model to demonstrate that homozygous knockout of the Tgfbr2 gene (Tgbr2(FspKO)) enhanced mammary tumor growth and metastasis. Here, we show for the first time a significant role for loss of one Tgfbr2 allele during multi-step mammary tumor progression. Heterozygous deletion of Tgfbr2 in stromal cells in MMTV-PyVmT transgenic mice (PyVmT/Tgfbr2(hetFspKO) mice) resulted in earlier tumor formation and increased stromal cell accumulation. In contrast to previous studies of Tgbr2(FspKO) fibroblasts, Tgfbr2(hetFspKO) fibroblasts did not significantly increase tumor growth, but enhanced lung metastasis in PyVmT transgenic mice and in co-transplantation studies with PyVmT mammary carcinoma cells. Furthermore, Tgfbr2(hetFspKO) fibroblasts enhanced mammary carcinoma cell invasiveness associated with expression of inflammatory cytokines including CXCL12 and CCL2. Analyses of Tgbr2(FspKO) and Tgfbr2(hetFspKO) fibroblasts revealed differences in the expression of factors associated with metastatic spread, indicating potential differences in the mechanism of action between homozygous and heterozygous deletion of Tgfbr2 in stromal cells. In summary, these studies demonstrate for the first time that loss of one Tgfbr2 allele in fibroblasts enhances mammary metastases in a multi-step model of tumor progression, and demonstrate the importance of clarifying the functional contribution of genetic alterations in stromal cells in breast cancer progression.

• TRAIL and interferon-alpha act synergistically to induce renal cell carcinoma apoptosis.

  Authors: Peter E Clark, Dina A Polosukhina, Kenneth Gyabaah, Harold L Moses, Andrew Thorburn, Roy Zent

  The Journal of urology. 09/2010; 184(3):1166-74.

  Despite modern targeted therapy metastatic renal cell carcinoma remains a deadly disease. Interferon-alpha (Calbiochem(R)) is currently used to treat this condition, mainly combined with the targetedDespite modern targeted therapy metastatic renal cell carcinoma remains a deadly disease. Interferon-alpha (Calbiochem(R)) is currently used to treat this condition, mainly combined with the targeted anti-vascular endothelial growth factor antibody bevacizumab. TRAIL (Apo2 ligand/tumor necrosis factor related apoptosis inducing ligand) (Calbiochem) is a novel antineoplastic agent now in early phase clinical trials. Interferon-alpha and TRAIL can act synergistically to kill cancer cells but to our knowledge this has never been tested in the context of renal cell carcinoma. We hypothesized that TRAIL and interferon-alpha could synergistically induce apoptosis in renal cell carcinoma cells. We treated renal cell carcinoma cell lines with recombinant TRAIL and/or interferon-alpha. Viability and apoptosis were assessed by MTS assay, flow cytometry and Western blot. Synergy was confirmed by isobologram. Interferon-alpha induced changes in renal cell carcinoma cell signaling were assessed by Western blot, flow cytometry and enzyme-linked immunosorbent assay. TRAIL and interferon-alpha acted synergistically to increase apoptotic cell death in renal cell carcinoma cells. Interferon-alpha treatment altered the ability of cells to activate extracellular signal-regulated kinase while inhibiting extracellular signal-regulated kinase with UO126 abrogated TRAIL and interferon-alpha apoptotic synergy. Interferon-alpha did not induce changes in TRAIL or death receptor expression, or change other known mediators of the intrinsic and extrinsic apoptotic cascade in the cells. TRAIL plus interferon-alpha synergistically induces apoptosis in renal cell carcinoma cells, which is due at least in part to interferon-alpha mediated changes in extracellular signal-regulated kinase activation. TRAIL and interferon-alpha combination therapy may be a novel approach to advanced renal cell carcinoma that warrants further testing in vivo.

• TGF-beta receptor deletion in the renal collecting system exacerbates fibrosis.

  Authors: Leslie Gewin, Nada Bulus, Glenda Mernaugh, Gilbert Moeckel, Raymond C Harris, Harold L Moses, Ambra Pozzi, Roy Zent

  Journal of the American Society of Nephrology : JASN. 08/2010; 21(8):1334-43.

  TGF-beta plays a key role in upregulating matrix production in injury-induced renal fibrosis, but how TGF-beta signaling in distinct compartments of the kidney, such as specific segments of theTGF-beta plays a key role in upregulating matrix production in injury-induced renal fibrosis, but how TGF-beta signaling in distinct compartments of the kidney, such as specific segments of the nephron, affects the response to injury is unknown. In this study, we determined the role of TGF-beta signaling both in development of the renal collecting system and in response to injury by selectively deleting the TGF-beta type II receptor in mice at the initiation of ureteric bud development. These mice developed normally but demonstrated a paradoxic increase in fibrosis associated with enhanced levels of active TGF-beta after unilateral ureteral obstruction. Consistent with this observation, TGF-beta type II receptor deletion in cultured collecting duct cells resulted in excessive integrin alphavbeta6-dependent TGF-beta activation that increased collagen synthesis in co-cultured renal interstitial fibroblasts. These results suggest that inhibiting TGF-beta receptor-mediated function in collecting ducts may exacerbate renal fibrosis by enhancing paracrine TGF-beta signaling between epithelial and interstitial cells.

• Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung.

  Authors: Hannah H Yan, Michael Pickup, Yanli Pang, Agnieszka E Gorska, Zhaoyang Li, Anna Chytil, Yipeng Geng, Jerome W Gray, Harold L Moses, Li Yang

  Cancer research. 08/2010; 70(15):6139-49.

  The mechanisms by which a primary tumor affects a selected distant organ before tumor cell arrival remain to be elucidated. This report shows that Gr-1+CD11b+ cells are significantly increased inThe mechanisms by which a primary tumor affects a selected distant organ before tumor cell arrival remain to be elucidated. This report shows that Gr-1+CD11b+ cells are significantly increased in lungs of mice bearing mammary adenocarcinomas before tumor cell arrival. In the premetastatic lungs, these immature myeloid cells significantly decrease IFN-gamma production and increase proinflammatory cytokines. In addition, they produce large quantities of matrix metalloproteinase 9 (MMP9) and promote vascular remodeling. Deletion of MMP9 normalizes aberrant vasculature in the premetastatic lung and diminishes lung metastasis. The production and activity of MMP9 is selectively restricted to lungs and organs with a large number of Gr-1+CD11b+ cells. Our work reveals a novel protumor mechanism for Gr-1+CD11b+ cells that changes the premetastatic lung into an inflammatory and proliferative environment, diminishes immune protection, and promotes metastasis through aberrant vasculature formation. Thus, inhibition of Gr-1+CD11b+ cells could normalize the premetastatic lung environment, improve host immunosurveillance, and inhibit tumor metastasis.

• Quantitative analysis of the secretome of TGF-beta signaling-deficient mammary fibroblasts.

  Authors: Baogang J Xu, Wenwei Yan, Bojana Jovanovic, Angel Q An, Nikki Cheng, Mary E Aakre, Yajun Yi, Jimmy Eng, Andrew J Link, Harold L Moses

  Proteomics. 07/2010; 10(13):2458-70.

  Transforming growth factor beta (TGF-beta) is a master regulator of autocrine and paracrine signaling pathways between a tumor and its microenvironment. Decreased expression of TGF-beta type IITransforming growth factor beta (TGF-beta) is a master regulator of autocrine and paracrine signaling pathways between a tumor and its microenvironment. Decreased expression of TGF-beta type II receptor (TbetaRII) in stromal cells is associated with increased tumor metastasis and shorter patient survival. In this study, SILAC quantitative proteomics was used to identify differentially externalized proteins in the conditioned media from the mammary fibroblasts with or without intact TbetaRII. Over 1000 proteins were identified and their relative differential levels were quantified. Immunoassays were used to further validate identification and quantification of the proteomic results. Differential expression was detected for various extracellular proteins, including proteases and their inhibitors, growth factors, cytokines, and extracellular matrix proteins. CXCL10, a cytokine found to be up-regulated in the TbetaRII knockout mammary fibroblasts, is shown to directly stimulate breast tumor cell proliferation and migration. Overall, this study revealed hundreds of specific extracellular protein changes modulated by deletion of TbetaRII in mammary fibroblasts, which may play important roles in the tumor microenvironment. These results warrant further investigation into the effects of inhibiting the TGF-beta signaling pathway in fibroblasts because systemic inhibition of TGF-beta signaling pathways is being considered as a potential cancer therapy.

• TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression.

  Authors: Li Yang, Yanli Pang, Harold L Moses

  Trends in immunology. 06/2010; 31(6):220-7.

  Transforming growth factor beta (TGF-beta) plays an important role in tumor initiation and progression, functioning as both a suppressor and a promoter. The mechanisms underlying this dual role ofTransforming growth factor beta (TGF-beta) plays an important role in tumor initiation and progression, functioning as both a suppressor and a promoter. The mechanisms underlying this dual role of TGF-beta remain unclear. TGF-beta exerts systemic immune suppression and inhibits host immunosurveillance. Neutralizing TGF-beta enhances CD8+ T-cell- and NK-cell-mediated anti-tumor immune responses. It also increases neutrophil-attracting chemokines resulting in recruitment and activation of neutrophils with an antitumor phenotype. In addition to its systemic effects, TGF-beta regulates infiltration of inflammatory/immune cells and cancer-associated fibroblasts in the tumor microenvironment causing direct changes in tumor cells. Understanding TGF-beta regulation at the interface of tumor and host immunity should provide insights into developing effective TGF-beta antagonists and biomarkers for patient selection and efficacy of TGF-beta antagonist treatment.

• Microdialysis combined with proteomics for protein identification in breast tumor microenvironment in vivo.

  Authors: Baogang J Xu, Wenwei Yan, Bojana Jovanovic, Aubie K Shaw, Qi A An, Jimmy Eng, Anna Chytil, Andrew J Link, Harold L Moses

  Cancer microenvironment : official journal of the International Cancer Microenvironment Society. 01/2010; 4(1):61-71.

  Tumor microenvironment constitutes a reservoir for proteins released from tumor cells and the host, which can contribute significantly to tumor growth and invasion. This study aims to apply a methodTumor microenvironment constitutes a reservoir for proteins released from tumor cells and the host, which can contribute significantly to tumor growth and invasion. This study aims to apply a method of combining in vivo microdialysis and proteomics to identify proteins in mammary tumor interstitial fluids, a major component of tumor microenvironment. In vivo microdialysis was performed in polyomavirus middle T antigen (PyVmT) transgenic mouse mammary tumors and age-matched control wild-type mammary glands. Over four hundred proteins were identified from the microdialysis perfusates, using the Multidimensional Protein Identification Technology. Osteopontin (OPN) is one of the proteins overexpressed in breast tumor perfusates, as confirmed with immunoassays. OPN was also found to be present in tumor-associated stroma in both PyVmT and human breast tumors, using immunohistochemistry. Specifically, fibroblasts were further shown to express OPN at both mRNA and protein levels. In vitro assays showed that OPN can stimulate PyVmT breast carcinoma cell proliferation and migration. Finally, the expression of OPN was significantly higher in the peripheral blood of mice bearing breast tumors, compared to wild-type mice. Overall, microdialysis combined with proteomics is a unique technique for identifying proteins in a tumor microenvironment in vivo. Mammary fibroblasts can secrete OPN, and its overexpression in mammary tumor microenvironment may contribute significantly to mammary tumor progression. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12307-010-0046-3) contains supplementary material, which is available to authorized users.

• Transforming growth factor beta (TGF-beta) and inflammation in cancer.

  Authors: Brian Bierie, Harold L Moses

  Cytokine & growth factor reviews. 12/2009;

  The transforming growth factor beta (TGF-beta) has been studied with regard to the regulation of cell behavior for over three decades. A large body of research has been devoted to the regulation ofThe transforming growth factor beta (TGF-beta) has been studied with regard to the regulation of cell behavior for over three decades. A large body of research has been devoted to the regulation of epithelial cell and derivative carcinoma cell populations in vitro and in vivo. TGF-beta has been shown to inhibit epithelial cell cycle progression and promote apoptosis that together significantly contribute to the tumor suppressive role for TGF-beta during carcinoma initiation and progression. TGF-beta is also able to promote an epithelial to mesenchymal transition that has been associated with increased tumor cell motility, invasion and metastasis. However, it has now been shown that loss of carcinoma cell responsiveness to TGF-beta stimulation can also promote metastasis. Interestingly, enhanced metastasis in the absence of a carcinoma cell response to TGF-beta stimulation has been shown to involve increased chemokine production resulting in recruitment of pro-metastatic myeloid derived suppressor cell (MDSC) populations to the tumor microenvironment at the leading invasive edge. When present, MDSCs enhance angiogenesis, promote immune tolerance and provide matrix degrading enzymes that promote tumor progression and metastasis. Further, the recruitment of MDSC populations in this context likely enhances the classic role for TGF-beta in immune suppression since the MDSCs are an abundant source of TGF-beta production. Importantly, it is now clear that carcinoma-immune cell cross-talk initiated by TGF-beta signaling within the carcinoma cell is a significant determinant worth consideration when designing therapeutic strategies to manage tumor progression and metastasis.

• TGF-beta helps cells fly solo.

  Authors: Lauren A Matise, Michael W Pickup, Harold L Moses

  Nature cell biology. 11/2009; 11(11):1281-4.

• GFAP-Cre-mediated activation of oncogenic K-ras results in expansion of the subventricular zone and infiltrating glioma.

  Authors: Ty W Abel, Cara Clark, Brian Bierie, Anna Chytil, Mary Aakre, Agnieszka Gorska, Harold L Moses

  Molecular cancer research : MCR. 06/2009; 7(5):645-53.

  A subset of neoplastic cells within human high-grade gliomas has features associated with stem cells. These cells may sustain glioma growth, and their stem-like properties may confer resistance toA subset of neoplastic cells within human high-grade gliomas has features associated with stem cells. These cells may sustain glioma growth, and their stem-like properties may confer resistance to standard glioma treatments. Whether glioma stem cells derive from indigenous neural stem cells (NSC), or from tumor cells that have reacquired stem cell-like properties, is unknown. However, signaling pathways that are tightly regulated and central to NSC biology, including the Ras/Raf/Erk pathway, are hyperactive and pathogenic in gliomagenesis. Furthermore, data in animal models suggests that, in some cases, tumors are initiated in the subventricular zone (SVZ), a stem/progenitor cell niche in the mature brain. We activated oncogenic K-ras in mouse glioneuronal precursor cells and adult SVZ cells using GFAP-Cre. GFAP-Cre+/K-ras(G12D) mice showed a marked expansion of glial fibriallary acidic protein (GFAP)- and TUJ1-expressing cell populations in the SVZ. In addition, mice developed intermediate grade, infiltrating glioma with 100% penetrance. Tumors were consistently located in the amygdalohippocampal region and nearby cortex, often in association with the lateral ventricle and expanded SVZ. Tumor cells expressed markers associated with neural progenitor cells, including Olig2, Bmi-1, and PDGFR-alpha. These data suggest that infiltrating tumor cells may arise from NSC transformed by activation of oncogenic K-ras in vivo.

• Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer.

  Authors: Brian Bierie, Christine H Chung, Joel S Parker, Daniel G Stover, Nikki Cheng, Anna Chytil, Mary Aakre, Yu Shyr, Harold L Moses

  The Journal of clinical investigation. 06/2009;

  In human breast cancer, loss of carcinoma cell-specific response to TGF-beta signaling has been linked to poor patient prognosis. However, the mechanisms through which TGF-beta regulates theseIn human breast cancer, loss of carcinoma cell-specific response to TGF-beta signaling has been linked to poor patient prognosis. However, the mechanisms through which TGF-beta regulates these processes remain largely unknown. In an effort to address this issue, we have now identified gene expression signatures associated with the TGF-beta signaling pathway in human mammary carcinoma cells. The results strongly suggest that TGF-beta signaling mediates intrinsic, stromal-epithelial, and host-tumor interactions during breast cancer progression, at least in part, by regulating basal and oncostatin M-induced CXCL1, CXCL5, and CCL20 chemokine expression. To determine the clinical relevance of our results, we queried our TGF-beta-associated gene expression signatures in 4 human breast cancer data sets containing a total of 1,319 gene expression profiles and associated clinical outcome data. The signature representing complete abrogation of TGF-beta signaling correlated with reduced relapse-free survival in all patients; however, the strongest association was observed in patients with estrogen receptor-positive (ER-positive) tumors, specifically within the luminal A subtype. Together, the results suggest that assessment of TGF-beta signaling pathway status may further stratify the prognosis of ER-positive patients and provide novel therapeutic approaches in the management of breast cancer.

• TGF-beta promotes cell death and suppresses lactation during the second stage of mammary involution.

  Authors: Brian Bierie, Agnieszka E Gorska, Daniel G Stover, Harold L Moses

  Journal of cellular physiology. 01/2009;

  Transforming growth factor beta (TGF-beta) ligands are known to regulate virgin mammary development and contribute to initiation of post-lactation involution. However, the role for TGF-beta duringTransforming growth factor beta (TGF-beta) ligands are known to regulate virgin mammary development and contribute to initiation of post-lactation involution. However, the role for TGF-beta during the second phase of mammary involution has not been addressed. Previously, we have used an MMTV-Cre transgene to delete exon 2 from the Tgfbr2 gene in mammary epithelium, however we observed a gradual loss of TbetaRII deficient epithelial cells that precluded an accurate study of the role for TGF-beta signaling during involution timepoints. Therefore, in order to determine the role for TGF-beta during the second phase of mammary involution we have now targeted TbetaRII ablation within mammary epithelium using the WAP-Cre transgene [TbetaRII((WKO))Rosa26R]. Our results demonstrated that TGF-beta regulates commitment to cell death during the second phase of mammary involution. Importantly, at day 3 of mammary involution the Na-Pi type IIb co-transporter (Npt2b), a selective marker for active lactation in luminal lobular alveolar epithelium, was completely silenced in the WAP-Cre control and TbetaRII((WKO))Rosa26R tissues. However, by day 7 of involution the TbetaRII((WKO))Rosa26R tissues had distended lobular alveoli and regained a robust Npt2b signal that was detected at the apical luminal surface. The Npt2b abundance and localization positively correlated with elevated WAP mRNA expression, suggesting that the distended alveoli were the result of an active lactation program rather than residual milk protein and lipid accumulation. In summary, the results suggest that an epithelial cell response to TGF-beta signaling regulates commitment to cell death and suppression of lactation during the second phase of mammary involution. J. Cell. Physiol. (c) 2008 Wiley-Liss, Inc.

• Transforming growth factor beta: tumor suppressor or promoter? Are host immune cells the answer?

  Authors: Li Yang, Harold L Moses

  Cancer research. 12/2008; 68(22):9107-11.

  Therapies targeting transforming growth factor beta (TGFbeta) signaling using neutralizing antibodies and small molecular inhibitors are in multiple clinical trails. However, TGFbeta is known to workTherapies targeting transforming growth factor beta (TGFbeta) signaling using neutralizing antibodies and small molecular inhibitors are in multiple clinical trails. However, TGFbeta is known to work as both a tumor suppressor and a tumor promoter, and current knowledge does not provide sufficient information on what factors mediate this switch in function and when this switch occurs. Recent advances in multiple disciplines suggest that immune cells from the tumor host may provide the answer.