Suppression of Tumor Development and Metastasis Formation in Mice Lacking the <i>S100A4(mts1)</i> Gene

Grum-Schwensen, Birgitte; Klingelhöfer, Jörg; Berg, Christian Hededam; El-Naaman, Christina; Grigorian, Mariam; Lukanidin, Eugene; Ambartsumian, Noona

doi:10.1158/0008-5472.can-04-4510

Cited by 208 publications

(165 citation statements)

References 45 publications

(64 reference statements)

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“…Through specific communication with cancer cells, CAFs can directly promote tumor initiation, progression and metastasis (Dimanche-Boitrel et al, 1994;Olaso et al, 1997;Olumi et al, 1999;Bhowmick et al, 2004;Kuperwasser et al, 2004;Grum-Schwensen et al, 2005;Orimo et al, 2005). CAFs secrete growth factors and ECM-degrading proteases to promote tumor growth and invasiveness.…”

Section: Introductionmentioning

confidence: 99%

miR-186 Regulates Glycolysis through Glut1 During the Formation of Cancer-associated Fibroblasts

Sun¹,

Hu²,

Xiong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Emerging evidence has suggested that glycolysis is enhanced in cancer-associated fibroblasts (CAF), and miR-186 is downregulated during the CAF formation. However, it is not clear whether miR-186 is involved in the regulation of glycolysis and what the role of miR-186 plays during the CAF formation. In this study, quantitative PCR analysises show miR-186 is downregulated during the CAF formation. Moreover, miR-186 targets the 3' UTR of Glut1, and its overexpression results in the degradation of Glut1 mRNA, which eventually reduces the level of Glut1 protein. On the other hand, knockdown of miR-186 increased the expression of Glut1. Both time course and dose response experiments also demonstrated that the protein and mRNA levels of Glut1 increase during CAF formation, according to Western blot and quantitative PCR analyses, respectively. Most importantly, besides the regulation on cell cycle progression, miR-186 regulates glucose uptake and lactate production which is mediated by Glut1. These observations suggest that miR-186 plays important roles in glycolysis regulation as well as cell cycle checkpoint activation.

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Section: Introductionmentioning

confidence: 99%

miR-186 Regulates Glycolysis through Glut1 During the Formation of Cancer-associated Fibroblasts

Sun¹,

Hu²,

Xiong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…Recent evidence shows that stromal cells may not be passive bystanders but might have an important role in modifying tumor growth. Many functional studies have demonstrated the importance of fibroblasts in cancer initiation 1 , progression [2][3][4] and metastases 5 . In animal models of prostate and breast cancers, oncogene-modified epithelial cells became malignant or showed enhanced growth when coinoculated with fibroblasts that were either oncogene induced 6 or derived from fresh human carcinoma tissues 2,3 (that is, CAFs).…”

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confidence: 99%

No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas

et al. 2008

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There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberrations in carcinoma-associated fibroblasts (CAFs), whereas other studies have reported very low or zero mutation rates. Resolution of this contentious area is of critical importance in terms of understanding both the basic biology of cancer as well as the potential clinical implications of CAF somatic alterations. We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis of CAFs derived from breast and ovarian carcinomas using a 500K SNP array platform. Our data show conclusively that LOH and copy number alterations are extremely rare in CAFs and cannot be the basis of the carcinomapromoting phenotypes of breast and ovarian CAFs. © 2008 Nature Publishing GroupCorrespondence should be addressed to I.G.C. ian.campbell@petermac.org. AUTHOR CONTRIBUTIONS I.G.C., I.H. and W.Q. designed the study and wrote the paper. W.Q. undertook the bulk of the experimental work including tissue microdissection, SNP genotyping and microsatellite analysis. K.P. provided cell lines, academic support and assisted in manuscript preparation. A.S., E.R.T., M.R. and K.L.G. assisted in SNP genotyping. However, not all studies have identified genetic alterations in CAFs; for example, one study did not find any clonally selected somatic genetic alterations in CAFs separated from fresh breast cancer biopsies using array comparative genomic hybridization (CGH) and SNP array analysis 17 , although these CAFs were epigenetically distinct from those from normal breast tissue, as demonstrated by subsequent genome-wide DNA methylation studies 18 .The evidence for somatic genetic alterations as important mediators of the CAF phenotype is controversial and conflicting. We hypothesized that the contradictory data may in part be a reflection of inherent technical limitations of the various methodologies used. Therefore, we took advantage of innovative SNP array-based technologies 19 to investigate in detail the genomic integrity of CAFs microdissected from fresh frozen primary human ovarian and breast cancers as well as short-term cultures of primary breast CAFs.We assessed the sensitivity of the Affymetrix 500K SNP array platform to detect copy number and LOH in the context of normal DNA contamination in a mixing experiment using tumor epithelial cell DNA from a microdissected primary ovarian cancer that was mixed with various ratios of matched normal DNA. This tumor harbors a complex copy number profile on chromosome 17, including regions of high level copy number gain and regions of LOH with and without associated copy number loss. As shown in Supplementary Figure 1a online, the single copy number gain was clearly visible at 70% tumor DNA, and the high level gain was still discernible at 25% tumor DNA. LOH w...

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“…1). Recently, it was shown that fibroblast-produced FSP-1 promotes tumor metastasis and that mammary carcinoma cells injected into FSP-1 -/-mice showed significant delay in tumor uptake and decreased tumor incidence 15 . Interestingly, coinjection of carcinoma cells with FSP-1 +/+ mouse embryonic fibroblasts (MEFs) partially restored the kinetics of tumor development and the ability to form metastases.…”

mentioning

confidence: 99%

Heterogeneity of stromal fibroblasts in tumor

Orimo

Weinberg

2007

Cancer Biology & Therapy

133

111

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Suppression of Tumor Development and Metastasis Formation in Mice Lacking the S100A4(mts1) Gene

Cited by 208 publications

References 45 publications

miR-186 Regulates Glycolysis through Glut1 During the Formation of Cancer-associated Fibroblasts

miR-186 Regulates Glycolysis through Glut1 During the Formation of Cancer-associated Fibroblasts

No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas

Heterogeneity of stromal fibroblasts in tumor

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