- Email: [email protected]
333 The Role of 5-Hydroxymethylcytosine and Tet Proteins in the Differentiation of the Intestinal Epithelium
AGA Abstracts
(1.23 versus 1.55 cells per hemi villus, p=0.03). There was no difference in enteroendocrine cell numbers in crypts, and no difference in Muc2 positive goblet cell numbers in fed versus unfed tissue. Paneth cells per hemi crypt were increased in unfed tissue (1.75 versus 0.76, p,0.02). Conclusions: Withdrawal of luminal nutrients resulted in increased paneth cell numbers and decreased s6 phosphorylation and proliferation in the stem cell compartment of human small intestine. As a critical component of the intestinal stem cell niche, Paneth cells appear to be shifting the stem cell fate from differentiation to self renewal in the nutrient deficient state.
cancer stem cell-like spheroid cells (CSC-LCs) formation were determined under the microscope. The levels of cytokines in the supernatant were measured using ELISA. Stable Stat3knockdown gastric cancer cell lines were generated. Gene expression was assessed by RTPCR and Western blot. Tumor growth in vivo was evaluated by using NOD/SCID xenograft mouse models. Results: Both BMFs and BMF-SCM significantly increased CSC-LCs formation in CD44+ CSCs, induced CSC-LCs formation in CD44- non-CSCs, and prevented CSC-LCs differentiation induced by serum. These CSC-LCs exhibited the features of self-renewal and epithelial-to-mesenchymal transition (EMT) and increased capacity of tumor formation in vivo. In a co-culture, the levels of IL-6 and HGF secreted by BMFs and TGF- β1 secreted by cancer cells were significantly increased in comparison to that secreted by cells cultured alone. Furthermore, BMF-SCM or recombinant (r) IL-6 activated Stat3 and upregulated mHGF expression in BMFs and TGF- β1 expression in cancer cells. rmHGF activated pStat3 in human and mouse cancer cells. In return, cancer cell conditioned medium (CCM) or rhTGF-β1 stimulated BMFs to produce IL-6 and HGF. Blockage of mHGF/c-met and JAK2/Stat3 pathways by specific neutralization antibodies or inhibitor significantly inhibited BMF-SCM-induced CSC-LCs formation of cancer cells. Knockdown of Stat3 in cancer cells significantly reduced BMF-SCM-induced CSC-LCs and inhibited BMF-promoted tumorigenesis and tumor growth. Importantly, the combinations of JAK2 inhibitor and TGF- β1 receptor inhibitor significantly inhibited BMF-promoted tumor growth. Conclusion: Our study uncovered IL-6/HGF and TGF-β1 signaling loop which plays critical role in reprogramming gastric cancer cells and BMF-promoted gastric cancer tumorigenesis (This study was supported by NIH R21CA149865, NSFC 91029718 and NSFC81272403 to SPTU and NIH RO1 CA133021 to CS Yang).
333 The Role of 5-Hydroxymethylcytosine and Tet Proteins in the Differentiation of the Intestinal Epithelium Rinho Kim, Karyn Sheaffer, Reina Aoki, Inchan Choi, Kyoung-Jae Won, Klaus H. Kaestner Background & Aims: DNA methylation at the 5 position of cytosine is a well-characterized epigenetic modification that is important for essential cellular processes including proliferation and differentiation. 5-hydroxymethylcytosine (5hmC) has been identified as an oxidation product of 5-methylcytosine (5mC) catalyzed by the Ten Eleven Translocation 1-3 (TET 13) family of enzymes in mammals. While 5hmC and TET proteins are required for normal embryonic development and hematopoiesis, their role in intestinal differentiation remains unknown. Our aim was to determine if, and to what extent, 5-hydroxymethylation of cytosine contributes to intestinal epithelial differentiation. Methods & Results: We examined global 5hmC levels by immunohistochemistry in the intestinal epithelium. 5hmC is enriched villi, but it is barely detectable in crypts. To investigate which Tet proteins cause these differential 5hmC levels, we isolated Lgr5-expressing stem and differentiated villus epithelial cells, and determined Tet1-3 mRNA levels using quantitative RT-PCR. Tet1 was highly expressed in Lgr5-expressing stem cells, but not in differentiated cells. Conversely, Tet2 and Tet3 were highly expressed in differentiated cells, but not in Lgr5-expressing stem cells. To determine 5hmC status genome-wide and correlate it with gene expression, we performed immunoprecipitation for hydroxymethylated DNA followed by high-throughput sequencing and mRNA sequencing in Lgr5-expressing stem cells and differentiated cells. A total of 1,410 differentially hydroxymethylated genes were identified between Lgr5-expressing stem cells and differentiated cells. During differentiation, genes that acquire 5hmC (n=1050, among them sucraseisomaltase) are mainly related with metabolic processes and associated with increased expression. Conclusion: We identified differential 5hmC and Tet1-3 expression levels between crypts and villi in the intestinal epithelium. We have determined the genome-wide 5hmC and gene expression profile of intestinal stem cells and differentiated cells. These data indicate that 5hmC levels are positively correlated with gene expression during differentiation of the intestinal epithelium, and suggest that conversion of 5mC to 5hmC might be a novel mechanism contributing to intestinal function and health.
336 Gremlin 1 Defines a Mesenchymal Stem Cell in the Gastrointestinal Tract, Bone and Tumor Microenvironment Daniel L. Worthley, Yiling Si, Michael Churchill, Samuel Asfaha, Nicholas Manieri, Christoph B. Westphalen, Yagnesh H. Tailor, Yoku Hayakawa, Jared Carpenter, Abhinav Nair, Guang Jin, Michael Quante, Mark A. Glaire, Bernhard W. Renz, Jean-Philippe Pradere, Juliane S. Troeger, Ryan Spurrier, Daniel E. Levin, Robert Schwabe, Tracy Grikscheit, Thaddeus S. Stappenbeck, Siddhartha Mukherjee, Timothy C. Wang Introduction: Bone marrow (BM) mesenchymal stem cells (MSCs) are both the origin of mesenchymal lineages and a functional regulator of the hematopoietic stem cell niche. We hypothesized that Grem1 expression would functionally define the MSC niche cell in the BM, gastrointestinal tract and tumor microenvironment. Methods: We made Grem1-BACCreERT, αSMA-BAC-CreERT, Grem1-BAC-EGFP-peptide 2A-DTR-peptide 2A-CreERT (Grem1-GDC) and Vimentin-BAC-CreERT transgenic lines. These mice were crossed to reporters and to Grem1fl/fl lines. The cellular fate and function of Grem1, αSMA and Vimentin expressing cells, is being analyzed in health, in several cancer models (AOM/DSS, H felis/MNU and metastasis models), colonic biopsy injury model and in tissue engineered small intestinal (TESI) grafts (Grem1-traced donor TESI). The specific role of Grem1 expression and cells is being examined in vivo (using conditional knock outs and diphtheria toxin (DTX)) and also in co-culture of intestinal organoids with intestinal MSCs. Results: Grem1 recombination was identified in the MSC enriched CD45/Ter119/CD31 triple negative, CD105+/CD140a double positive fraction. Grem1-EGFP identified a discrete population of perisinusoidal cells, the recognized site of BM MSCs. Grem1-recombined cells are enriched for colony forming unit-fibroblasts. Grem1-recombined cells have multilneage potential in vitro (adipocytes, osteoblasts, chondrocytes, myofibroblasts). At 24 hours post-tamoxifen induction (throughout the gastrointestinal tract) there were single Grem1 recombined stromal cells found immediately subjacent to the basement membrane near the organ-specific epithelial stem cell niche. These recombined cells gradually expand over the next 12 months to completely trace the periglandular fibroblast sheath. In both the gut and bone marrow, perinatal tamoxifen induction led to dramatically accelerated lineage tracing, defining this cell as an MSC in both bone and bowel development. Syngeneic tumorigenicity and carcinogenesis studies in our Grem1-BAC-specific lines revealed that Grem1 marked a cellular origin of cancer-associated mesenchyme. Many cancer-associated fibroblasts, however, arose from other (αSMA+ or Vimentin+) adult lineages. The relationship between Grem1+ MSCs in development and future CAFs is being tested. Ablation of Grem1-DTR cells with 200ng DTX caused rapid death due to multiorgan failure. Conditional knock out studies are proceeding. Conclusions: Grem1-expression labels a specific and vital MSC in the bone and gut that can give rise to multiple mesenchymal lineages during development and in the peritumoral stroma. We are currently examining the functional relevance of these cells and Grem1 production in supporting the normal and pathological stem cell niche in the bone marrow, gut and tumor microenvironment.
334 Construction of a PRO-Survival Wnt-Secreting Niche by Intestinal Cancer Cells Requires Cell Division Cycle 42 Ryotaro Sakamori, Nan Gao BACKGROUND & AIMS: Acquisition of mutations in adenomatous polyposis coli (APC) or β-catenin is likely the initiating event during the development of the majority of human colorectal cancers. Despite the revelation of various somatic mutations in advanced colorectal cancer genome, it is still not clear what molecular adaptations in the initial mutant cells render them immediate capacity for survival and outgrowth. Cell division cycle 42 (Cdc42) is an APC-binding small GTPase that has long been postulated to impact on APC function and aberrant cellular migration, but its in vivo role in colorectal cancer development has not been established. A survey of colorectal adenocarcinoma patients revealed overexpression of Cdc42 in 60% of the pathological samples, with ~79% of the poorly differentiated cancers demonstrating high Cdc42 levels. We aimed to investigate the hypothesis that the initial mutant colorectal cancer cells exploit the pleiotropic effects mediated by Cdc42-controlled cellular machinery to accomplish a program of survival adaptation. METHODS: Mice that bear either APC-inactivating or β-catenin dominant-active mutation were used as models of colorectal cancer. The effects of genetic attenuation of Cdc42 on the tumorigenesis of these colorectal cancer models were analyzed at histological and molecular levels. RESULTS: APC or β-catenin mutant intestines showed abnormally elevated Cdc42 activation in early stages of tumorigenesis. Canonical Wnt ligands or constitutively activated Wnt signaling significantly stimulate Cdc42 activation. High levels of Cdc42 were indispensible for the morphogenesis of numerous crypt-like hyperplastic foci centered on a core of Wnt-secreting cells, and critical for mutant colorectal cancer cells to override spindle checkpoint and develop aneuploidy. Genetic attenuation of Cdc42 in vivo alleviated intestinal polyposis and prolonged the survival of the animals. These effects are attributable to elevated mitotic cell deaths triggered specifically in the crypt-like microadenoma foci. CONCLUSIONS: Cdc42 and Wnt signaling reciprocate to drive the formation of pro-survival niche for clonal expansion of tumor cells with autocrine Wnt signaling capacity.
337 Insulin-Like Growth Factor Binding Protein-3 Regulates Esophageal Tumor Initiating Capability via a Novel Insulin-Like Growth Factor-Independent Antioxidant Activity Hideaki Kinugasa, Mitsuteru Natsuizaka, Shingo Kagawa, Kelly A. Whelan, Harry Subramanian, Sanders Chang, Shinya Ohashi, Seiji Naganuma, J. Alan Diehl, Phyllis A. Gimotty, Andres J. Klein-Szanto, Meenhard Herlyn, Hiroshi Nakagawa
335
Introduction: Insulin-like growth factor binding protein (IGFBP)-3 is often localized to hypoxic intratumoral areas surrounding necrotic foci in esophageal squamous cell carcinoma (ESCC)(FASEB J. 2012;26:2620-30). Excessive IGFBP3 may induce apoptosis by inhibiting insulin-like growth factor (IGF)-mediated pro-survival signaling; however, IGFBP3 can promote epithelial-mesenchymal transition (EMT) in an IGF-independent manner (Carcinogenesis. 2010;31:1344-53). There exists a highly tumorigenic subset of ESCC cells defined by high expression of CD44 (CD44H cell) and mesenchymal characteristics. We investigated how IGFBP3 may influence tumor initiating capability of ESCC cells in the hypoxic tumor microenvironment. Methods: Ras-transformed human esophageal cells (RasL) and ESCC cell lines (TE11 and others) were exposed to either hydrogen peroxide (H2O2) or hypoxia (0.5% O2) following treatment with recombinant human IGFBP3 (rhIGFBP3) or genetic
The IL-6/STAT3/HGF and TGF-β1 Signaling Loop Mediates Crosstalk Between Cancer Cells and Bone Marrow-Derived Myofibroblasts That Regulate Cancer Stem Cells and Gastric Tumorigenesis Liming Zhu, Jindong Shi, Huanyu Jin, Anna B Liu, Hong Wang, Hyunseung Pyo, Timothy C. Wang, Chung S. Yang, Yunlin Wu, Jing Ye, Yan Bo Zhu, Shuiping Tu Background: Bone marrow-derived myofibroblasts (BMFs) play an important role in tumor development. In this study, we investigated the roles of BMFs in tumor initiation and underlying mechanims. Methods: Human and mouse cancer cells were either co-cultured with murine BMFs or cultured in a BMF conditioned stem cell medium (BMF-SCM). The
AGA Abstracts
S-70
(1.23 versus 1.55 cells per hemi villus, p=0.03). There was no difference in enteroendocrine cell numbers in crypts, and no difference in Muc2 positive goblet cell numbers in fed versus unfed tissue. Paneth cells per hemi crypt were increased in unfed tissue (1.75 versus 0.76, p,0.02). Conclusions: Withdrawal of luminal nutrients resulted in increased paneth cell numbers and decreased s6 phosphorylation and proliferation in the stem cell compartment of human small intestine. As a critical component of the intestinal stem cell niche, Paneth cells appear to be shifting the stem cell fate from differentiation to self renewal in the nutrient deficient state.
cancer stem cell-like spheroid cells (CSC-LCs) formation were determined under the microscope. The levels of cytokines in the supernatant were measured using ELISA. Stable Stat3knockdown gastric cancer cell lines were generated. Gene expression was assessed by RTPCR and Western blot. Tumor growth in vivo was evaluated by using NOD/SCID xenograft mouse models. Results: Both BMFs and BMF-SCM significantly increased CSC-LCs formation in CD44+ CSCs, induced CSC-LCs formation in CD44- non-CSCs, and prevented CSC-LCs differentiation induced by serum. These CSC-LCs exhibited the features of self-renewal and epithelial-to-mesenchymal transition (EMT) and increased capacity of tumor formation in vivo. In a co-culture, the levels of IL-6 and HGF secreted by BMFs and TGF- β1 secreted by cancer cells were significantly increased in comparison to that secreted by cells cultured alone. Furthermore, BMF-SCM or recombinant (r) IL-6 activated Stat3 and upregulated mHGF expression in BMFs and TGF- β1 expression in cancer cells. rmHGF activated pStat3 in human and mouse cancer cells. In return, cancer cell conditioned medium (CCM) or rhTGF-β1 stimulated BMFs to produce IL-6 and HGF. Blockage of mHGF/c-met and JAK2/Stat3 pathways by specific neutralization antibodies or inhibitor significantly inhibited BMF-SCM-induced CSC-LCs formation of cancer cells. Knockdown of Stat3 in cancer cells significantly reduced BMF-SCM-induced CSC-LCs and inhibited BMF-promoted tumorigenesis and tumor growth. Importantly, the combinations of JAK2 inhibitor and TGF- β1 receptor inhibitor significantly inhibited BMF-promoted tumor growth. Conclusion: Our study uncovered IL-6/HGF and TGF-β1 signaling loop which plays critical role in reprogramming gastric cancer cells and BMF-promoted gastric cancer tumorigenesis (This study was supported by NIH R21CA149865, NSFC 91029718 and NSFC81272403 to SPTU and NIH RO1 CA133021 to CS Yang).
333 The Role of 5-Hydroxymethylcytosine and Tet Proteins in the Differentiation of the Intestinal Epithelium Rinho Kim, Karyn Sheaffer, Reina Aoki, Inchan Choi, Kyoung-Jae Won, Klaus H. Kaestner Background & Aims: DNA methylation at the 5 position of cytosine is a well-characterized epigenetic modification that is important for essential cellular processes including proliferation and differentiation. 5-hydroxymethylcytosine (5hmC) has been identified as an oxidation product of 5-methylcytosine (5mC) catalyzed by the Ten Eleven Translocation 1-3 (TET 13) family of enzymes in mammals. While 5hmC and TET proteins are required for normal embryonic development and hematopoiesis, their role in intestinal differentiation remains unknown. Our aim was to determine if, and to what extent, 5-hydroxymethylation of cytosine contributes to intestinal epithelial differentiation. Methods & Results: We examined global 5hmC levels by immunohistochemistry in the intestinal epithelium. 5hmC is enriched villi, but it is barely detectable in crypts. To investigate which Tet proteins cause these differential 5hmC levels, we isolated Lgr5-expressing stem and differentiated villus epithelial cells, and determined Tet1-3 mRNA levels using quantitative RT-PCR. Tet1 was highly expressed in Lgr5-expressing stem cells, but not in differentiated cells. Conversely, Tet2 and Tet3 were highly expressed in differentiated cells, but not in Lgr5-expressing stem cells. To determine 5hmC status genome-wide and correlate it with gene expression, we performed immunoprecipitation for hydroxymethylated DNA followed by high-throughput sequencing and mRNA sequencing in Lgr5-expressing stem cells and differentiated cells. A total of 1,410 differentially hydroxymethylated genes were identified between Lgr5-expressing stem cells and differentiated cells. During differentiation, genes that acquire 5hmC (n=1050, among them sucraseisomaltase) are mainly related with metabolic processes and associated with increased expression. Conclusion: We identified differential 5hmC and Tet1-3 expression levels between crypts and villi in the intestinal epithelium. We have determined the genome-wide 5hmC and gene expression profile of intestinal stem cells and differentiated cells. These data indicate that 5hmC levels are positively correlated with gene expression during differentiation of the intestinal epithelium, and suggest that conversion of 5mC to 5hmC might be a novel mechanism contributing to intestinal function and health.
336 Gremlin 1 Defines a Mesenchymal Stem Cell in the Gastrointestinal Tract, Bone and Tumor Microenvironment Daniel L. Worthley, Yiling Si, Michael Churchill, Samuel Asfaha, Nicholas Manieri, Christoph B. Westphalen, Yagnesh H. Tailor, Yoku Hayakawa, Jared Carpenter, Abhinav Nair, Guang Jin, Michael Quante, Mark A. Glaire, Bernhard W. Renz, Jean-Philippe Pradere, Juliane S. Troeger, Ryan Spurrier, Daniel E. Levin, Robert Schwabe, Tracy Grikscheit, Thaddeus S. Stappenbeck, Siddhartha Mukherjee, Timothy C. Wang Introduction: Bone marrow (BM) mesenchymal stem cells (MSCs) are both the origin of mesenchymal lineages and a functional regulator of the hematopoietic stem cell niche. We hypothesized that Grem1 expression would functionally define the MSC niche cell in the BM, gastrointestinal tract and tumor microenvironment. Methods: We made Grem1-BACCreERT, αSMA-BAC-CreERT, Grem1-BAC-EGFP-peptide 2A-DTR-peptide 2A-CreERT (Grem1-GDC) and Vimentin-BAC-CreERT transgenic lines. These mice were crossed to reporters and to Grem1fl/fl lines. The cellular fate and function of Grem1, αSMA and Vimentin expressing cells, is being analyzed in health, in several cancer models (AOM/DSS, H felis/MNU and metastasis models), colonic biopsy injury model and in tissue engineered small intestinal (TESI) grafts (Grem1-traced donor TESI). The specific role of Grem1 expression and cells is being examined in vivo (using conditional knock outs and diphtheria toxin (DTX)) and also in co-culture of intestinal organoids with intestinal MSCs. Results: Grem1 recombination was identified in the MSC enriched CD45/Ter119/CD31 triple negative, CD105+/CD140a double positive fraction. Grem1-EGFP identified a discrete population of perisinusoidal cells, the recognized site of BM MSCs. Grem1-recombined cells are enriched for colony forming unit-fibroblasts. Grem1-recombined cells have multilneage potential in vitro (adipocytes, osteoblasts, chondrocytes, myofibroblasts). At 24 hours post-tamoxifen induction (throughout the gastrointestinal tract) there were single Grem1 recombined stromal cells found immediately subjacent to the basement membrane near the organ-specific epithelial stem cell niche. These recombined cells gradually expand over the next 12 months to completely trace the periglandular fibroblast sheath. In both the gut and bone marrow, perinatal tamoxifen induction led to dramatically accelerated lineage tracing, defining this cell as an MSC in both bone and bowel development. Syngeneic tumorigenicity and carcinogenesis studies in our Grem1-BAC-specific lines revealed that Grem1 marked a cellular origin of cancer-associated mesenchyme. Many cancer-associated fibroblasts, however, arose from other (αSMA+ or Vimentin+) adult lineages. The relationship between Grem1+ MSCs in development and future CAFs is being tested. Ablation of Grem1-DTR cells with 200ng DTX caused rapid death due to multiorgan failure. Conditional knock out studies are proceeding. Conclusions: Grem1-expression labels a specific and vital MSC in the bone and gut that can give rise to multiple mesenchymal lineages during development and in the peritumoral stroma. We are currently examining the functional relevance of these cells and Grem1 production in supporting the normal and pathological stem cell niche in the bone marrow, gut and tumor microenvironment.
334 Construction of a PRO-Survival Wnt-Secreting Niche by Intestinal Cancer Cells Requires Cell Division Cycle 42 Ryotaro Sakamori, Nan Gao BACKGROUND & AIMS: Acquisition of mutations in adenomatous polyposis coli (APC) or β-catenin is likely the initiating event during the development of the majority of human colorectal cancers. Despite the revelation of various somatic mutations in advanced colorectal cancer genome, it is still not clear what molecular adaptations in the initial mutant cells render them immediate capacity for survival and outgrowth. Cell division cycle 42 (Cdc42) is an APC-binding small GTPase that has long been postulated to impact on APC function and aberrant cellular migration, but its in vivo role in colorectal cancer development has not been established. A survey of colorectal adenocarcinoma patients revealed overexpression of Cdc42 in 60% of the pathological samples, with ~79% of the poorly differentiated cancers demonstrating high Cdc42 levels. We aimed to investigate the hypothesis that the initial mutant colorectal cancer cells exploit the pleiotropic effects mediated by Cdc42-controlled cellular machinery to accomplish a program of survival adaptation. METHODS: Mice that bear either APC-inactivating or β-catenin dominant-active mutation were used as models of colorectal cancer. The effects of genetic attenuation of Cdc42 on the tumorigenesis of these colorectal cancer models were analyzed at histological and molecular levels. RESULTS: APC or β-catenin mutant intestines showed abnormally elevated Cdc42 activation in early stages of tumorigenesis. Canonical Wnt ligands or constitutively activated Wnt signaling significantly stimulate Cdc42 activation. High levels of Cdc42 were indispensible for the morphogenesis of numerous crypt-like hyperplastic foci centered on a core of Wnt-secreting cells, and critical for mutant colorectal cancer cells to override spindle checkpoint and develop aneuploidy. Genetic attenuation of Cdc42 in vivo alleviated intestinal polyposis and prolonged the survival of the animals. These effects are attributable to elevated mitotic cell deaths triggered specifically in the crypt-like microadenoma foci. CONCLUSIONS: Cdc42 and Wnt signaling reciprocate to drive the formation of pro-survival niche for clonal expansion of tumor cells with autocrine Wnt signaling capacity.
337 Insulin-Like Growth Factor Binding Protein-3 Regulates Esophageal Tumor Initiating Capability via a Novel Insulin-Like Growth Factor-Independent Antioxidant Activity Hideaki Kinugasa, Mitsuteru Natsuizaka, Shingo Kagawa, Kelly A. Whelan, Harry Subramanian, Sanders Chang, Shinya Ohashi, Seiji Naganuma, J. Alan Diehl, Phyllis A. Gimotty, Andres J. Klein-Szanto, Meenhard Herlyn, Hiroshi Nakagawa
335
Introduction: Insulin-like growth factor binding protein (IGFBP)-3 is often localized to hypoxic intratumoral areas surrounding necrotic foci in esophageal squamous cell carcinoma (ESCC)(FASEB J. 2012;26:2620-30). Excessive IGFBP3 may induce apoptosis by inhibiting insulin-like growth factor (IGF)-mediated pro-survival signaling; however, IGFBP3 can promote epithelial-mesenchymal transition (EMT) in an IGF-independent manner (Carcinogenesis. 2010;31:1344-53). There exists a highly tumorigenic subset of ESCC cells defined by high expression of CD44 (CD44H cell) and mesenchymal characteristics. We investigated how IGFBP3 may influence tumor initiating capability of ESCC cells in the hypoxic tumor microenvironment. Methods: Ras-transformed human esophageal cells (RasL) and ESCC cell lines (TE11 and others) were exposed to either hydrogen peroxide (H2O2) or hypoxia (0.5% O2) following treatment with recombinant human IGFBP3 (rhIGFBP3) or genetic
The IL-6/STAT3/HGF and TGF-β1 Signaling Loop Mediates Crosstalk Between Cancer Cells and Bone Marrow-Derived Myofibroblasts That Regulate Cancer Stem Cells and Gastric Tumorigenesis Liming Zhu, Jindong Shi, Huanyu Jin, Anna B Liu, Hong Wang, Hyunseung Pyo, Timothy C. Wang, Chung S. Yang, Yunlin Wu, Jing Ye, Yan Bo Zhu, Shuiping Tu Background: Bone marrow-derived myofibroblasts (BMFs) play an important role in tumor development. In this study, we investigated the roles of BMFs in tumor initiation and underlying mechanims. Methods: Human and mouse cancer cells were either co-cultured with murine BMFs or cultured in a BMF conditioned stem cell medium (BMF-SCM). The
AGA Abstracts
S-70