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

Nakagawa, Hidewaki; Liyanarachchi, Sandya; Davuluri, Ramana V.; Auer, Herbert; Martin, Edward W.; Chapelle, Albert de la; Frankel, Wendy L.

doi:10.1038/sj.onc.1208013

Cited by 208 publications

(188 citation statements)

References 36 publications

Supporting

Mentioning

180

Contrasting

Unclassified

Order By: Relevance

“…The formation of CAFs involves several important features: (a) the expression of fibroblast markers vimentin, FSP1 and FAP; (b) the expression of activation marker α‐SMA; (c) the expression of aggressive/invasive markers including TNC; (d) an increase in cytokine and growth factor expression including IL‐8, IL‐6, SDF‐1, VEGF, TGF‐β, HGF, and FGF‐2; and (e) the reprogramming of ECM proteins and matrix remodeling proteins 4, 35, 48, 49, 50, 51, 52, 53. Interestingly, we have observed that the mRNA expression of α‐SMA, collagen I, or HIF‐1α was not altered by H. pylori ( cagA−vacA−) in contrast to the moderate increase in HSP‐70 mRNA expression possibly due to the “cytoprotective” properties of bacterial wall product LPS 54, 55.…”

Section: Discussionmentioning

confidence: 99%

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

et al. 2018

View full text Add to dashboard Cite

BackgroundMajor human gastrointestinal pathogen Helicobacter pylori (H. pylori) colonizes the gastric mucosa causing inflammation and severe complications including cancer, but the involvement of fibroblasts in the pathogenesis of these disorders in H. pylori‐infected stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts. Their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue; however, the interaction between H. pylori and fibroblasts remains unknown. We determined the effect of coincubation of normal rat gastric fibroblasts with alive H. pylori (cagA+vacA+) and H. pylori (cagA−vacA−) strains on the differentiation of these fibroblasts into cells possessing characteristics of cancer‐associated fibroblasts (CAFs) able to induce epithelial‐mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM‐1).Materials and MethodsThe panel of CAFs markers mRNA was analyzed in H. pylori (cagA+vacA+)‐infected fibroblasts by RT‐PCR. After insert coculture of differentiated fibroblasts with RGM‐1 cells from 24 up to 48, 72, and 96 hours, the mRNA expression for EMT‐associated genes was analyzed by RT‐PCR.ResultsThe mRNA expression for CAFs markers was significantly increased after 72 hours of infection with H. pylori (cagA+vacA+) but not H. pylori (cagA−vacA−) strain. Following coculture with CAFs, RGM‐1 cells showed significant decrease in E‐cadherin mRNA, and the parallel increase in the expression of Twist and Snail transcription factors mRNA was observed along with the overexpression of mRNAs for TGFβR, HGFR, FGFR, N‐cadherin, vimentin, α‐SMA, VEGF, and integrin‐β1.Conclusion Helicobacter pylori (cagA+vacA+) strain induces differentiation of normal fibroblasts into CAFs, likely to initiate the EMT process in RGM‐1 epithelial cell line.

show abstract

Section: Discussionmentioning

confidence: 99%

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

et al. 2018

View full text Add to dashboard Cite

show abstract

“…28 Nakagawa et al generated expression profiles of cancer-associated stromal fibroblasts by using oligochip arrays and found that 170 cancer-related genes were up-regulated in CRC. 29 These data suggest that we should regard the gene expression in surrounding stroma tissues as different from that in cancer cells, and gene expression analysis of the stroma tissue should be included into the consideration of molecular changes in cancer development.…”

Section: Discussionmentioning

confidence: 99%

5‐fluorouracil‐related gene expression levels in primary colorectal cancer and corresponding liver metastasis

Kuramochi

Hayashi

Uchida

et al. 2006

Intl Journal of Cancer

View full text Add to dashboard Cite

Gene expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT) have been shown to be associated with response to 5-fluorouracil-based therapies. Analyzing these gene expression levels in liver metastases is important to obtain the best prediction of therapy. Our aim was to determine how TS, DPD, TP and OPRT gene expression levels in primary colorectal cancer (CRC) were related to those in liver metastases. Formalin-fixed, paraffin-embedded tumor specimens from 31 pairs of primary CRC and corresponding liver metastases were dissected by using laser-captured microdissection. RNA was extracted and cDNA was prepared by reverse-transcription. Quantitation of target gene and internal reference gene was performed using real-time PCR. No significant difference was seen between median mRNA expression levels of TS, DPD, TP and OPRT in primary cancer and those in corresponding liver metastases (median value: TS 1.48 vs. When matched tissue sets were compared on an individual basis, there was a significant correlation for TS mRNA expression between primary cancer and corresponding liver metastases (rs 5 0.52, p 5 0.0026). However, no correlation was seen between matched sets for DPD, TP or OPRT. Significant correlation was seen between DPD and TP expression levels in both primary CRC (rs 5 0.38, p 5 0.03) and liver metastases (rs 5 0.72, p < 0.0001). A good prediction of TS mRNA levels in liver metastases can be obtained by measuring those of primary CRC, although no correlation was seen for DPD, TP and OPRT. ' 2006 Wiley-Liss, Inc.Key words: 5-fluorouracil; colorectal cancer; liver metastases; thymidylate synthase; dihydropyrimidine dehydrogenase Colorectal cancer (CRC) is the fourth most common malignancy and the second leading cause of cancer death in the United States. 1 The most commonly used chemotherapeutic drug for CRC is 5-fluorouracil (5-FU), which has been used for more than 40 years and still remains an important component of many standard treatments. 2 The main mechanism of 5-FU activity involves inhibition of thymidylate synthase (TS), which is the rate-limiting enzyme in the synthesis of thymine nucleotides.A number of genes have been investigated as predictive factors for response to 5-FU-related drugs and as prognostic markers. Leichman et al. 3 had previously shown that high gene expression levels (mRNA levels) of TS identified tumors that would be nonresponsive to 5-FU based therapy. Dihydropyrimidine dehydrogenase (DPD) is responsible for the degradation of the pyrimidines, uracil and thymine, as well as the inactivation of the 5-FU, and has been shown in several studies to be associated with response to 5-FU-based therapies. [4][5][6][7] Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor, has a role in tumor angiogenesis but also catalyzes the conversion of 5-FU to the more active nucleoside form and has been shown to be an in vitro determinant of 5-FU activity...

show abstract

“…15 In particular, CRC-associated stromal fibroblasts have been found to upregulate vascular endothelial growth factor (VEGF-A), which is significantly correlated with lymphovascular invasion (LVI), angiogenic spread and poor prognosis. [16][17][18] LVI in CRC has been linked to lymph node metastasis 19,20 and liver metastasis; 21 hence, accurate assessment of LVI in primary CRC is important in the diagnosis and treatment of patients. Moreover, because stromal cells of the CRC microenvironment has been found to have an important role in the development of blood and lymphatic vessels associated with LVI, 22 we investigated stromal SPARC expression and its relationship to LVI.…”

Section: Lymphovascular Invasion Of Colorectal Cancer Is Correlated Tmentioning

confidence: 99%

Lymphovascular invasion of colorectal cancer is correlated to SPARC expression in the tumor stromal microenvironment

Yoshimura

Nagahara²,

Kuo³

et al. 2011

Epigenetics

View full text Add to dashboard Cite

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

Cited by 208 publications

References 36 publications

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

5‐fluorouracil‐related gene expression levels in primary colorectal cancer and corresponding liver metastasis

Lymphovascular invasion of colorectal cancer is correlated to SPARC expression in the tumor stromal microenvironment

Contact Info

Product

Resources

About