Hepatic carcinoma-associated fibroblasts promote an adaptative response in colorectal cancer cells that inhibit proliferation and apoptosis: nonresistant cells die by nonapoptotic cell death.

Carcinoma-associated fibroblasts (CAFs) are important contributors of microenvironment in determining the tumor's fate. This study aimed to compare the influence of liver microenvironment and primary tumor microenvironment on the behavior of colorectal carcinoma. Conditioned medium (CM) from normal colonic fibroblasts (NCFs), CAFs from primary tumor (CAF-PT) or liver metastasis (CAF-LM) were obtained. We performed functional assays to test the influence of each CM on colorectal cell lines. Microarray and gene set enrichment analysis (GSEA) were performed in DLD1 cells cultured in matched CM. In DLD1 cells, CAF-LM CM compared with CAF-PT CM and NCF led to a more aggressive phenotype, induced the features of an epithelial-to-mesenchymal transition more efficiently, and stimulated migration and invasion to a greater extent. Sustained stimulation with CAF-LM CM evoked a transient G(2)/M cell cycle arrest accompanied by a reduction of apoptosis, inhibition of proliferation, and decreased viability of SW1116, SW620, SW480, DLD1, HT-29, and Caco-2 cells and provoked nonapoptotic cell death in those cells carrying KRAS mutations. Cells resistant to CAF-LM CM completely changed their morphology in an extracellular signal-regulated protein kinase-dependent process and depicted an increased stemness capacity alongside the Wnt pathway stimulation. The transcriptomic profile of DLD1 cells treated with CAF-LM CM was associated with Wnt and mitogen-activated protein kinase pathways activation in GSEA. Therefore, the liver microenvironment induces more efficiently the aggressiveness of colorectal cancer cells than other matched microenvironments do but secondarily evokes cell death. Resistant cells displayed higher stemness capacity.

[1]  A. Sood,et al.  Cancer-associated fibroblasts and their putative role in potentiating the initiation and development of epithelial ovarian cancer. , 2011, Neoplasia.

[2]  H. Tian,et al.  Inhibition of lung cancer cell proliferation mediated by human mesenchymal stem cells. , 2011, Acta biochimica et biophysica Sinica.

[3]  M. Andreeff,et al.  Concise Review: Dissecting a Discrepancy in the Literature: Do Mesenchymal Stem Cells Support or Suppress Tumor Growth? , 2010, Stem cells.

[4]  K. Kang,et al.  Human umbilical cord blood mesenchymal stem cell-derived extracellular matrix prohibits metastatic cancer cell MDA-MB-231 proliferation. , 2010, Cancer letters.

[5]  Louis Vermeulen,et al.  Wnt activity defines colon cancer stem cells and is regulated by the microenvironment , 2010, Nature Cell Biology.

[6]  T. Mahmoudi,et al.  MAP3K1 functionally interacts with Axin1 in the canonical Wnt signalling pathway , 2010, Biological chemistry.

[7]  Aimee L. Alphonso,et al.  Stromal cells and integrins: conforming to the needs of the tumor microenvironment. , 2009, Neoplasia.

[8]  L. Buscail,et al.  Adult Stromal Cells Derived from Human Adipose Tissue Provoke Pancreatic Cancer Cell Death both In Vitro and In Vivo , 2009, PloS one.

[9]  J. Pollard,et al.  Microenvironmental regulation of metastasis , 2009, Nature Reviews Cancer.

[10]  James W. Clancy,et al.  ADP-ribosylation factor 6 regulates tumorigenic and invasive properties in vivo. , 2009, Cancer research.

[11]  C. Shao,et al.  Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1 , 2009, Leukemia.

[12]  Nathan M Sherer,et al.  Cytonemes and tunneling nanotubules in cell-cell communication and viral pathogenesis. , 2008, Trends in cell biology.

[13]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[14]  Zhili Xu,et al.  Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model , 2008, Cell Research.

[15]  J. Huot,et al.  Role of Cancer Microenvironment in Metastasis: Focus on Colon Cancer , 2008, Cancer Microenvironment.

[16]  Shahin Rafii,et al.  Migratory neighbors and distant invaders: tumor-associated niche cells. , 2008, Genes & development.

[17]  Jill P. Mesirov,et al.  GSEA-P: a desktop application for Gene Set Enrichment Analysis , 2007, Bioinform..

[18]  J. Grande,et al.  Involvement of RNA helicases p68 and p72 in colon cancer. , 2007, Cancer research.

[19]  D. Newgreen,et al.  Induction of epithelial to mesenchymal transition in PMC42-LA human breast carcinoma cells by carcinoma-associated fibroblast secreted factors , 2007, Breast Cancer Research.

[20]  E. Lam,et al.  Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth , 2007, Leukemia.

[21]  M. Fukuzawa,et al.  Artificially accumulated beta-catenin inhibits proliferation and induces neurite extension of neuroblastoma cell line NB-1 via up-regulation of trkA. , 2006, Oncology reports.

[22]  J. Blenis,et al.  MAPK signal specificity: the right place at the right time. , 2006, Trends in biochemical sciences.

[23]  Raghu Kalluri,et al.  Fibroblasts in cancer , 2006, Nature Reviews Cancer.

[24]  Robert Tibshirani,et al.  A simple method for assessing sample sizes in microarray experiments , 2006, BMC Bioinformatics.

[25]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[26]  I. Fabregat,et al.  Snail blocks the cell cycle and confers resistance to cell death. , 2004, Genes & development.

[27]  David Botstein,et al.  Gene expression patterns and gene copy number changes in dermatofibrosarcoma protuberans. , 2003, The American journal of pathology.

[28]  P. Morin.  Drug resistance and the microenvironment: nature and nurture. , 2003, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[29]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[30]  Joerg Huelsken,et al.  The Wnt signalling pathway , 2002, Journal of Cell Science.

[31]  I. Roninson,et al.  p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells , 2000, Oncogene.

[32]  K Watanabe,et al.  Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[33]  N. Ip,et al.  Developmental and tissue‐specific expression of DEAD box protein p72 , 2000, Neuroreport.

[34]  E. Nishida,et al.  Cyclin-dependent kinase 2 (Cdk2) is required for centrosome duplication in mammalian cells , 1999, Current Biology.

[35]  B. Wouters,et al.  Apoptosis, p53, and tumor cell sensitivity to anticancer agents. , 1999, Cancer research.

[36]  N. Ahn,et al.  Transformation of mammalian cells by constitutively active MAP kinase kinase. , 1994, Science.

[37]  C. Bucana,et al.  Modulation of the invasive phenotype of human colon carcinoma cells by organ specific fibroblasts of nude mice. , 1992, Differentiation; research in biological diversity.

[38]  M. Cobb,et al.  Evidence for a Ras-dependent extracellular signal-regulated protein kinase (ERK) cascade. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[39]  M. Reed,et al.  Paracrine influence of human breast stromal fibroblasts on breast epithelial cells: Secretion of a polypeptide which stimulates reductive 17β‐oestradiol dehydrogenase activity , 1988, International Journal of Cancer.

[40]  I. Roninson,et al.  Effects of p 21 Waf 1 / Cip 1 / Sdi 1 on cellular gene expression : Implications for carcinogenesis , senescence , and age-related diseases , 2000 .