Die Identifizierung von spezifischen nukleären Matrix Proteinen (NMP) in humanen prämalignen Polypen des Kolons: Ein vielversprechender Weg zur Früherkennung von Kolon Karzinomen

Abstract

IntroductionMost colon cancers arise within preexisting adenomatous polyps or adenomas. Thereby, the carcinogenesis of colon cancer favors a strategy of early detection. Detection of early stage colorectal cancer, and finding and removal of pre-malignant adenomatous polyps have been shown to beneficially impact on colorectal cancer incidence and mortality. The identification of an early tumor marker that would allow reliable early cancer detection could lead to a diagnostic assay that would greatly aid in the management of this disease. The nuclear matrix is the residual framework scaffolding of the nucleus and consists of the peripheral lamins and pore complexes, an internal ribonucleic protein network and residual nucleoli. NMPs have been demonstrated to participate in many vital cellular functions, such as steroid hormone binding, gene transcription and translation. Most of the nuclear matrix proteins identified to date are common to all cell types, but several identified NMPs are tissue and cell line specific [1, 2]. Cell type-specific „fingerprinting“ of aberrant nuclear matrix proteins and their appearance in cancer development has led to the analysis of nuclear matrix protein composition of a variety of tumors in an effort to determine whether these proteins can be developed as diagnostic markers for cancer.We have identified four specific nuclear matrix proteins (NMP: CC2, CC3, CC4, CC5) that distinguish colon cancer from normal adjacent mucosa, and from normal mucosa in subjects without colon cancer [3]. The objective of this study was to describe and characterize the nuclear matrix protein profile in pre-malignant adenomatous colon polyps. In particular, we wanted to determine when in the adenoma-carcinoma sequence can the unique colon cancer NMP’s be identified.Material and MethodsUsing 2-D gel analysis with following silver staining 20 colon polyps (one juvenile polyp, six tubular adenoma (TA), seven tubulovillous adenoma (TVA), six tubulovillous adenoma with focal high grade dysplasia (HGD), and two human colon cancer cell lines (CaCo2, Cx-1), were analyzed for the presence of these specific nuclear matrix proteins.ResultsThe protein spot CC2 was not seen in any of the pre-malignant polyps, but was present in 80% of colon cancers (N = 10). The protein spot CC5 was present in only 2 pre-malignant TVA with HGD and in one TA, but was present in all colon cancer tissues (10/10). CC3 and CC4 were present in most adenomas, regardless of advancement and in all colon cancer tissues. None of the nuclear matrix proteins were seen in the juvenile polyp, which is not a precursor of colon cancer. The cell line CaCo2 expressed CC3 and CC4 and the cell line CX-1 CC2, CC3 and CC4.ConclusionIt is known that the risk of malignancy within an adenomatous polyp correlates with the sizes, histologic type, and degree of dysplasia. CC2 and CC5 are proteins that are expressed at the junction of an advanced adenoma and invasive colon cancer. CC3 and CC4 are expressed earlier in the development of adenomatous polyps. All four spots are specific for colon cancer and are not found in normal adjacent or normal donor tissue or in the juvenile polyp. The fact that these proteins are shown already in the pre-malignant phase of colon cancer indicates them as useful early detection target. Additionally the functional identification of these proteins could lead to new knowledge in the carciogenesis in colon cancer. The generation of antibodies to them is being actively pursued. Development of an assay to these nuclear matrix proteins may serve as a new promising method for early detection of colon cancer.