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The lack of genetic alterations in carcinoma-associated fibroblasts suggests that the role of the tumour microenvironment in driving tumorigenesis may depend on epigenetic rather than somatic changes in stromal cells.
Does the key role of the tumour microenvironment in driving tumorigenesis depend on somatic genetic alterations in the stromal cells? The evidence has been divided, but new research using high-resolution single nucleotide polymorphism (SNP) array technology shows that carcinoma-associated fibroblasts (CAFs) display little evidence of changes in copy number or loss of heterozygosity (LOH).
CAFs can promote tumorigenesis in epithelial cells even when isolated from the tumour, implying that genetic or epigenetic changes in the CAFs might be responsible. Several studies have reported high frequencies of genomic aberrations in CAFs, but other studies have found only epigenetic changes. Campbell and colleagues argue that previous studies that found genomic changes suffered from technical limitations concerning both the cell samples studied and the techniques for detecting changes.
So, the authors used microdissected CAF samples — fresh frozen rather than paraffin-embedded — from breast and ovarian cancers. They also looked at short-term cultures of primary breast CAFs, the advantage of these being that their tumour-promoting phenotype could be verified. These samples were hybridized to Affymetrix 500K SNP arrays, which can detect both copy number changes and LOH. In contrast to the epithelial cancer cells, none of the CAFs from the breast cancer samples, and only one of the ovarian CAF samples and one of the cell cultures, showed evidence of genetic changes. Moreover, when the authors looked at specific mutation hot spots that had been reported in these cancer types, they found no changes.
The few changes that the authors did see do not necessarily contribute to tumour promotion: they might be selectively neutral. The fact that most CAFs showed no changes implies that genetic changes in CAFs are not required and suggest that epigenetic changes may instead be responsible. Further studies using similar technologies on other cancer samples, and studies of epigenetic changes, should help answer the question of how CAFs exert their effect.
ORIGINAL RESEARCH PAPER
- Qiu , W. et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nature Genet. 13 Apr 2008 (doi:10.1038/ng.117) | Article |
FURTHER READING
- Kalluri , R. & Zeisberg , M. Fibroblasts in cancer. Nature Rev. Cancer 6, 392–401 (2006) | Article |