CD44 variant 6 expression predicts response to treatment in advanced colorectal cancer
Department of Oncology and Radiotherapy, Turku University Central Hospital, Turku, Finland.Oncology Reports (Impact Factor: 2.3). 02/2004; 11(1):41-5. DOI: 10.3892/or.11.1.41
CD44 has diverse functions in cell-cell and cell-matrix interactions and may be a determinant of metastatic and invasive behaviour in carcinomas. CD44 variant 6 (CD44v6) has been postulated to be involved in both carcinogenesis and tumor progression. Therefore, we have examined CD44v6 expression in tumors from 57 patients with advanced colorectal cancer who received one of two chemotherapy regimes (either irinotecan alone or irinotecan and 5-flurouracil with folinic acid). CD44v6 expression was determined immunohistochemically in 57 paraffin-embedded primary tumor sections and assessed using image analysis software. Strong expression levels of CD44v6 were seen in 24/57 (42%) of tumors, moderate levels in 17/57 (30%), weak levels in 9/57 (16%) and no expression was seen in 7/57 (12%). The pattern of staining was predominantly cytoplasmic, 7/57 tumors also exhibited membrane specific expression. A significant association was found between tumor CD44v6 expression and treatment response (Fisher's exact test p=0.01). Only 1/12 patients with no or weak tumor expression of CD44v6 showed a response to treatment whereas 20/41 (49%) patients with moderate or strong CD44v6 expression responded to treatment. Evaluation of CD44v6 expression of locally advanced and metastatic colorectal tumors may enable the clinician to identify and select patients that will show the best response to irinotecan based chemotherapy.
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ABSTRACT: Progress in the treatment of colon cancer depends on the development of target-based molecules built on an improved understanding of the molecular biology of the disease. Defining end points for chemotherapy resistance is needed as drug resistance develops quickly and patients demonstrate variation in response to chemotherapy. Many techniques that measure a marker's preponderance have been developed including biochemical, immunohistochemical, genomics, proteomics or a combination thereof. However, standardization of these techniques that measure either genes or their protein products is urgently needed. This article reviews several markers (TS,TP, DPD, FT, EGFR, VEGF, CD44v6, TRAIL, microsatellite instability, allelic deletions, oncogenes and suppressor genes [c-myc, Ki-Ras, p53, p21, Topo I, Topo IIalpha, Fos, hMLH1, Bcl-2/Bax and MDR1], MDR-related proteins [Pgp, MRP and LRP], genomic polymorphisms [XPD, ERCC1, GSTP1 and TS 3 -UTR] and COX-;2) that influence DNA metabolism, DNA damage, programmed cell death, the immune or vascular system, or lead to mutations. When combined together and tested by newly developed genomic and proteomic approaches, many of these markers provide a more sensitive indicative predictor of response than when evaluated separately or by older biochemical, immunohistologic or morphologic methods. A global approach involving the simultaneous testing of several predictive multimarkers will provide critical information for improving chemotherapy to alleviate suffering from this disease.Expert Review of Molecular Diagnostics 06/2005; 5(3):353-75. DOI:10.1586/1473718.104.22.1683 · 3.52 Impact Factor
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ABSTRACT: Immunohistochemical analysis of the expression of E-cadherin, beta-catenin, and CD-44v6 proteins was carried out for evaluating the metastatic potential of colorectal cancer cells. Specific features of expression, distribution, and interactions of adhesive molecules in primary tumors of the large intestine and their metastases in the liver and lymph nodes were studied. Reduction and complete absence of E-cadherin expression were much more often observed in patients with colorectal cancer with metastases in the liver than in patients without metastases. Cytoplasmic immunoreactivity and nuclear translocation of beta-catenin were increased in more than 80% cases with colorectal adenocarcinoma with metastases. These changes in the expression of E-cadherin and beta-catenin in tumor cells can be regarded as factors of unfavorable prognosis of colorectal cancer. No significant relationship between expression of CD-44v6 protein and metastatic potential of cancer cells was detected.Bulletin of Experimental Biology and Medicine 07/2005; 139(6):706-10. · 0.36 Impact Factor
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ABSTRACT: Prolonged exposure to 17beta-estradiol (E2) is a key etiological factor for human breast cancer. The biological effects and carcinogenic effects of E2 are mediated via estrogen receptors (ERs), ERalpha and ERbeta. Anti-estrogens, e.g. tamoxifen, and aromatase inhibitors have been used to treat ER-positive breast cancer. While anti-estrogen therapy is initially successful, a major problem is that most tumors develop resistance and the disease ultimately progresses, pointing to the need of developing alternative drugs targeting to other critical targets in breast cancer cells. We have identified that Na+, K+-ATPase, a plasma membrane ion pump, has unique/valuable properties that could be used as a potentially important target for breast cancer treatment: (a) it is a key player of cell adhesion and is involved in cancer progression; (b) it serves as a versatile signal transducer and is a target for a number of hormones including estrogens and (d) its aberrant expression and activity are implicated in the development and progression of breast cancer. There are several lines of evidence indicating that ouabain and related digitalis (the potent inhibitors of Na+, K+-ATPase) possess potent anti-breast cancer activity. While it is not clear how the suggested anti-cancer activity of these drugs work, several observations point to ouabain and digitalis as being potential ER antagonists. We critically reviewed many lines of evidence and postulated a novel concept that Na+, K+-ATPase in combination with ERs could be important targets of anti-breast cancer drugs. Modulators, e.g. ouabain and related digitalis could be useful to develop valuable anti-breast cancer drugs as both Na+, K+-ATPase inhibitors and ER antagonists.Breast Cancer Research and Treatment 04/2006; 96(1):1-15. DOI:10.1007/s10549-005-9053-3 · 3.94 Impact Factor
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