Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions

Abstract

Although numerous studies have reported that high frequencies of loss of heterozygosity (LOH) at various chromosomal arms have been identified in breast cancer, differential LOH in the neoplastic epithelial and surrounding stromal compartments has not been well examined. Using laser capture microdissection, which enables separation of neoplastic epithelium from surrounding stroma, we microdissected each compartment of 41 sporadic invasive adenocarcinomas of the breast. Frequent LOH was identified in both neoplastic epithelial and/or stromal compartments, ranging from 25 to 69% in the neoplastic epithelial cells, and from 17 to 61% in the surrounding stromal cells, respectively. The great majority of markers showed a higher frequency of LOH in the neoplastic epithelial compartment than in the stroma, suggesting that LOH in neoplastic epithelial cells might precede LOH in surrounding stromal cells. Furthermore, we sought to examine pair-wise associations of particular genetic alterations in either epithelial or stromal compartments. Seventeen pairs of markers showed statistically significant associations. We also propose a genetic model of multi-step carcinogenesis for the breast involving the epithelial and stromal compartments and note that genetic alterations occur in the epithelial compartments as the earlier steps followed by LOH in the stromal compartments. Our study strongly suggests that interactions between breast epithelial and stromal compartments might play a critical role in breast carcinogenesis and several genetic alterations in both epithelial and stromal compartments are required for breast tumour growth and progression.

Possible alternative carcinogenesis pathway featuring microsatellite instability in colorectal cancer stroma

“…However, the recent finding of frequent genetic changes in mammary stromal tissue in breast cancer patients (Moinfar et al, 2000), and the demonstration that inflammation-associated stroma promotes conversion of colonic adenoma cells to adenocarcinoma cells in nude mice (Okada et al, 2000) suggest a more complex scenario. Our present study showed that MSI in stromal and epithelial elements can occur independently in sporadic colorectal cancers, in line with the previous findings for breast carcinomas (Kurose et al, 2001). Further, while MSI in the epithelium tended to correlate with differentiation and the Dukes' stage, the inverse was the case for MSI in stroma.…”

Macro-environment of breast carcinoma: frequent genetic alterations in the normal appearing skins of patients with breast cancer

“…1 Since publication of our previous observation, several other groups have confirmed the occurrence of genetic abnormalities in the normal-appearing stromal cells close to the breast carcinomas. [2][3][4][5] In the current study, we provide, for the first time, evidence of common genetic alterations in the tumor-free and morphologically normal-appearing mammary skin of the patients with breast cancer. These data have implications for understanding of tumorigenesis in general and of breast cancer in particular.…”

“…[1][2][3][4][5] These data strongly suggest that genetic abnormalities in microenvironmental tissues with subsequent alterations of reciprocal interactions between epithelial and stromal cells play a key role in the tumorigenesis of breast cancer. In our previous study, we showed that loss of heterozygosity (LOH) frequently occurs in the tumor-free and normal-appearing epithelial and mesenchymal tissue components close to and away (at least 15-mm distance) from the breast cancer tissues.…”

Isolation and characterization of human breast tumor-derived endothelial cells

“…However, it has become clear from preliminary trials that a number of anti-angiogenic drugs or strategies can lose their activity over time (26,27). Several potential mechanisms have been evocated, such as the great redundancy of tumor-secreted angiogenic growth factors and the anti-apoptotic properties of TEC dependent either on direct tumor-endothelial cell interaction or on epigenetic changes occurring after persistent cell activation (28). Recently, it has been reported that tumor endothelium has, at the molecular level, distinct characteristics from normal endothelial cells (15) and may be resistant to apoptosis (14,29).…”