Dynamic stromal‐epithelial interactions during progression of MCF10DCIS.com xenografts

Abstract

cells form comedo type ductal carcinoma in situ in immune-deficient mice before forming invasive ductal carcinoma. As the lesions mature, both stromal and epithelial cells undergo phenotypic changes detected by immunohistochemistry. Myofibroblasts are present before the formation of carcinoma in situ and after development of invasive carcinoma. MCF10DCIS. com lesions develop a myoepithelial layer prior to exhibiting a basement membrane surrounding the ductal mass. TGFb1 is initially expressed by the epithelial cells but is expressed by stroma in invasive carcinoma. Stromal derived factor-1 is detected in epithelial cells in early carcinoma in situ but is produced in stromal cells in invasive carcinoma. The receptor CXCR4 is expressed by epithelial cells in the xenografts at all times, as is the hepatocyte growth factor receptor c-met. MCF10DCIS.com xenografts illustrate the dynamic interplay of epithelium and stroma in the development of carcinoma in situ and subsequent invasive carcinoma. Although the phenotype of the epithelial cells may be dependent upon the stroma, the malignant epithelium induces the development of the stroma necessary for progression to the invasive stage. ' 2007 Wiley-Liss, Inc.Key words: breast cancer; carcinoma in situ; MCF10DCIS.com; progression; stroma; xenograft The natural history of cancer is thought to involve multiple sequential genetic changes including mutations, loss of heterozygosity and amplification of gene copy number as well as epigenetic changes such as hypermethylation of promoter regions. In many epithelial cancers a series of abnormal histologic changes can be identified and associated with increased risk of progressing to malignant disease. It has been assumed that each stage accumulates additional genetic anomalies. The first recognized lesion with increased risk for breast cancer is hyperplasia ( a 4-fold increased risk for atypical ductal hyperplasia) but genetic anomalies are rare. ErbB2 is rarely detected in benign lesions. 1-3 However, overexpression of erbB2 is frequent in DCIS and IDC. Studies of mixed lesions, containing both in situ and invasive components, invariably report that the 2 components express erbB2 coordinately. 4-6 A similar pattern occurs for cyclin D1 expression; rare in benign hyperplastic lesions but frequent in both DCIS and IDC and expressed coordinately in both in situ and invasive components of mixed lesions. 7,8 Recent studies suggest that nearly all genetic alterations have occurred by the time of DCIS formation. Comparative genomic hybridization analysis of breast DCIS and IDC found no significant difference in the number of chromosomal abnormalities, although the frequency of a few specific changes varied in high grade versus low grade DCIS and between DCIS and concurrent IDC. 9 A more recent study confirmed that DCIS is genetically advanced. Allelic imbalance of 52 microsatellite markers of chromosomal regions commonly lost in breast cancer increased significantly between atypical ductal hyperplasia and DCIS but not between DCIS an...

Potential Proinvasive or Metastatic Effects of Preclinical Antiangiogenic Therapy Are Prevented by Concurrent Chemotherapy

“…Female yellow fluorescent protein (YFP) SCID mice (37) were bred in-house from breeding pairs generously provided by Dr. Janusz Rak (McGill University, Montreal, Quebec, Canada). Mice at 6 to 8 weeks of age were used.…”

Ocimum gratissimumretards breast cancer growth and progression and is a natural inhibitor of matrix metalloproteases

“…35 MCF10ADCIS. com human breast cancer cells produce tumors that resemble clinical comedo-DCIS and recapitulate the temporal sequence of progression from in situ to invasive cancer [35][36][37] when injected into nude mice.…”

“…MCF10ADCIS.com cells (obtained from Cell Core, Karmanos Cancer Institute) were cultured in DMEM-F12 medium supplemented with 5% horse serum. 36,37 All cells were maintained in a humidified chamber with 95% air and 5% CO 2 at 37°C.…”

Cullin-3 protein expression levels correlate with breast cancer progression

“…The MCF10DCIS.com cells provide an appropriate model to study progression because these xenografts produce tumors resembling clinical comedo DCIS that progress to invasive cancer. [17][18][19] The cells develop into lesions at day 6, that progress to DCIS (day 17), advanced comedo DCIS (day 36) and invasive cancer (day 56). 19 In our study, tumors were excised from the mice at day 6, 17, 36, 47 and 56.…”

“…[17][18][19] The cells develop into lesions at day 6, that progress to DCIS (day 17), advanced comedo DCIS (day 36) and invasive cancer (day 56). 19 In our study, tumors were excised from the mice at day 6, 17, 36, 47 and 56. Cullin-3 protein expression was then determined by immunohistochemistry.…”