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Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles

Oncogene volume 23, pages 7366–7377 (2004)Cite this article

Abstract

The cancer microenvironment and interaction between cancer and stromal cells play critical roles in tumor development and progression. The molecular features of cancer stroma are less well understood than those of cancer cells. Cancer-associated stromal fibroblasts are the predominant component of stroma associated with colon cancer and its functions remain unclear. Fibroblast cell cultures were established from metastatic colon cancer in liver, liver away from the metastatic lesions, and skin from three patients with metastatic colorectal cancer. We generated expression profiles of cancer-associated fibroblasts using oligochip arrays and compared them to those of uninvolved fibroblasts. The conditioned media from the cancer-associated fibroblast cultures enhanced proliferation of colon cancer cell line HCT116 to a greater extent than cultures from uninvolved fibroblasts. In microarray expression analysis, cancer-associated fibroblasts clustered tightly into one group and skin fibroblasts into another. Approximately 170 of 22 000 genes were up-regulated in cancer-associated fibroblasts (fold change>2, P<0.05) as compared to skin fibroblasts, including many genes encoding cell adhesion molecules, growth factors, and COX2. By immunohistochemistry in-vivo, we confirmed COX2 and TGFB2 expression in cancer-associated fibroblasts in metastatic colon cancer. The distinct molecular expression profiles of cancer-associated fibroblasts in colon cancer metastasis support the notion that these fibroblasts form a favorable microenvironment for cancer cells.

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Abbreviations

BrdU:

bromodeoxyuridine

CAFs:

Cancer-associated stromal fibroblasts

DAPI:

4’6-diamidino-2-phenylindole dihydrochloride

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

PBS:

phosphate-buffered saline

RT–PCR:

reverse transcriptase–polymerase chain reaction

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Acknowledgements

We thank J Palatini and D Newsom for their technical assistance with microarrays, and S Jones for her technical assistance with immunohistochemistry. This work was supported by grants CA67941 and CA16058 from the National Institutes of Health.

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Authors and Affiliations

  1. Division of Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, 43210, OH, USA

    Hidewaki Nakagawa, Sandya Liyanarachchi, Ramana V Davuluri, Herbert Auer & Albert de la Chapelle

  2. Department of Surgical Oncology, The Ohio State University, Columbus, 43210, OH, USA

    Edward W Martin Jr

  3. Department of Pathology, The Ohio State University, Columbus, 43210, OH, USA

    Wendy L Frankel

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  1. Hidewaki Nakagawa
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Correspondence to Wendy L Frankel.

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Nakagawa, H., Liyanarachchi, S., Davuluri, R. et al. Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles. Oncogene 23, 7366–7377 (2004). https://doi.org/10.1038/sj.onc.1208013

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