- It is intended for research use only
- The kit consists of 2 assays
- The Colorectal Cancer Assay 1 measures human MMP-7 and GDF-15 in serum
- The Colorectal Cancer Assay 2 measures human TFF3 and IGFBP-2 in serum
- Additional sample types may be suitable but have not been validated
- The total assay time is less than 1.5 hours
- Components of the kit are provided ready to use, concentrated or lyophilized
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.
Human trefoil factor 3 (TFF3, also known as intestinal trefoil factor) belongs together with TFF1 and TFF2 to a small group of mucin-associated peptides. TFF3 contains seven cysteine residues, six of which form disulfide bonds to create a characteristic three-leafed structure. Due to its compact structure, TFF3 is extremely resistant toward acids, proteolytical cleavage or heat degradation. Monomeric form of TFF3 consists of 60 amino acids and has 6.7 kDa, while the dimer (13.1 kDa) consists of 118 amino acids.
TFF3 is expressed mainly in gastrointestinal tract, in the mucous cells of the small and large intestine, where it maintains the integrity of mucous layer and in cooperation with mucins protects the gastrointestinal epithelial cells against various injurious agents. However, TFF3 was also detected in salivary glands, posterior pituitary gland and in the inner ear. Secretion of TFF3 is triggered by the presence of certain inflammation mediators and neurotransmitters.
Over-expression of TFF3 occurs at the sites of damage of the gastrointestinal tract, e.g. peptic ulcer or inflammatory bowel disease. Patients suffering from these diseases have increased levels of TFF3 in serum. TFF3 was reported to be over-expressed also in patients with various neoplasms including intestinal, pancreatic and prostate carcinomas. On the contrary, its expression decreases in thyroid follicular carcinomas. In vitro studies showed that in breast cancer cells, expression of TFF3 is regulated by the level of estrogen.
Recent study with human and rodent pancreatic islet β-cells has demonstrated that TFF3 overexpression increases their proliferation. Both major forms of diabetes involve a decline in islet β-cells mass and their controlled expansion would have great potential utility for treatment of this diseases.
Insulin-like growth factor (IGF) binding proteins (IGFBPs) are a family of proteins (six for humans) that bind and serve as carriers of IGFs, prolonging the IGF half-life in the circulation and modulating local IGF concentrations and activities. These proteins share a conserved three-domain structure, consisting of two conserved cysteine-rich domains at N- and C-terminals that are required for IGF binding and a nonconserved central domain that separates them. In humans, IGFBP3 is the most abundant and IGFBP2 is the second most abundant IGFBP in the circulation.
Because IGFBP-2 is a secretory protein, its increased expression in tumor tissues may be reflected in its concentrations in blood. IGFBP2 has been shown to promote tumorigenesis , cancer cell invasion, metastasis, cancer stem cell expansion, and tumor angiogenesis in various types of cancers. Indeed, IGFBP2 is overexpressed in the tumor tissues. Moreover, elevated serum or plasma IGFBP2 levels have been observed in patients with glioma, prostate cancer, ovarian cancer, and colorectal cancer. Other results showed that blood IGFBP2 levels were significantly higher in lung cancer patients than in healthy controls. Increased expression of IGFBP2 is implicated in either a shorter overall survival time or resistance to chemotherapy. Together, those results suggest that IGFBP2 could be a common oncogenic protein for various types of cancers.
Clinical use and areas of investigation :
- Colorectal cancer
- Pancreatic cancer
- Diabetes mellitus
- Kidney tubular injury