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Pancreatic Cancer Panel

Matrix metalloproteinases (MMPs) constitute a family of structurally related zinc-dependent endopeptidases capable of degrading basement membrane and all components of the extracellular matrix. Tissue inhibitors of metalloproteinases (TIMPs) inhibit the proteolytic activity of MMPs. MMPs perform multiple roles including tissue remodeling, repair, and modulation of immune responses. In healthy tissues, MMPs are rarely expressed. Excessive MMP production has been reported in diverse inflammatory conditions such as cancer, chronic obstructive pulmonary disease, sarcoidosis, interstitial lung disease, arthritis, and atherosclerosis. It has been linked to the development of metastases and is also considered to play a role in tumorigenesis and tumor progression. MMP-7 is a 28 kDa protein consisting of 250 amino acids. MMP-7 has been found to be over-expressed in several tumors, such as those associated with esophageal, cholangiocarcinoma, gastric, colon, prostate and bladder cancer. The overexpression of MMP-7 is significantly associated with metastasis and the 1-year survival rate in pancreatic cancer. Saarialho-Kere et al. (1996) have reported enhanced expression of MMP-7 in gastrointestinal ulcers, suggesting a significant role in epithelial remodelling occurring in gastrointestinal ulcerations. Matsuno et al. (2003) have reported that MMP-7 appears to be expressed only in the epithelial cells on the edge of ulcers and indicates the degree of inflammation in ulcerative colitis. Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor b (TGF-b) cytokine superfamily. GDF-15 was originally cloned as macrophage-inhibitory cytokine 1 (MIC-1) and later also identified as placental TGF-b, placental bone morphogenetic protein (PLAB), nonsteroidal anti-inflammatory drug-activated gene 1, and prostate-derived factor. GDF-15 is synthesized as a 62-kDa precursor protein, then cleavage and secreted as 25-kDa disulfide-linked dimmer. GDF-15 is produced in low amounts under baseline conditions in most tissues such as brain, liver, kidney, pancreas, but not normally in many other organs including the heart. It is highly expressed in placenta and moderately in prostate. GDF-15 is also upregulated by other cardiovascular events triggering oxidative stress, including pressure overload, and atherosclerosis. Serum GDF-15 concentrations increase in maternal serum with advancing gestation in normal pregnancy. Increased GDF-15 expression has been documented in a variety of epithelial cell lines, including breast, pancreas, colorectal, and prostate cancers. Microarray studies have revealed increased expression of GDF-15 in patients with breast cancer, and serum GDF-15 levels are the best single predictor of the presence of pancreatic carcinoma. In the case of prostate cancer, serum GDF-15 levels increase with progression of disease to metastasis. In colon cancer, increasing GDF-15 expression is associated with the progression of colonic adenomas to invasive cancer and subsequent metastasis, with serum levels at presentation being an independent predictor of subsequent disease-free status and overall survival. Midkine (MK, also called neurite growth promoting factor 2, NEGF-2), a product of a retinoic acid responsive gene, is a secreted 13 kDa protein belonging to the family of heparin binding growth/differen­tiation factors. Midkine is composed of two domains held together by disulfide linkages. The C-terminally located domain contains two heparin binding sites and is usually responsible for midkine activity. Part of the MK activity is enhanced by dimerization of MK. Midkine has been found in vertebrates from human to zebrafish and is most strongly expressed in midgestation. In the adult MK expression is restricted. In addition to normal development, MK is also involved in the pathogenesis of diseases, e.g. inflammatory diseases, human carcinomas such as esophageal, stomach, colon, pancreatic, thyroid, lung,

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