الفهرس 
KallikreinsOnly 14 pages are availabe for public view
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Abstract
H
uman tissue kallikreins (KLK) are attracting increased attention owing to their association with various forms of cancer and other diseases. The human tissue kallikreins represent the largest contiguous cluster of protease genes in the human genome.
Human kallikrein 1, human kallikrein 2 and prostate-specific antigen (Kallikrein 3), were the first members of this family to be studied. Between 1994 and 2001, the kallikrein family expanded to include 15 genes and a complete description of the human kallikrein locus was reported. These newly discovered kallikreins all map to the same chromosomal region (19q13.4) as the three classical kallikreins.
All the KLK genes share many common characteristics, including: five coding exons, similar or identical coding exon lengths, and conserved protease catalytic triad residues His, Asp and Ser in exons 1, 3 and 5, respectively.
Using Northern blot, RT-PCR, and ELISA methodologies, it has been shown that tissue kallikreins are expressed in multiple organs. Kallikrein proteins have also been found in biological fluids such as serum, seminal plasma, and milk of lactating women, confirming that they are secreted proteins.
The KLK proteins were first described for their kininogenase activity that generates the vasoactive peptides bradykinin (BK) or kallidin (Lys-BK) from kininogens. Kinins induce vasodilation and increase vascular permeability, participating in regulation of blood pressure and inflammation.
Today, the tissue kallikreins have come to denote a group of structurally related serine proteases that are part of the specific gene cluster, mainly due to sequence and structural similarity, and they are not necessarily enzymes with kininogenase activity. In fact, it appears that in the KLK family, it is only KLK1 which has significant kininogenase activity.
Kallikreins participate in physiological proteolytic cascades such as the kallikrein - kinin system, hormone processing, skin antimicrobial function, semen liquefaction and skin desquamation. Kallikreins also have a role in some pathological conditions such as diabetes, cardiovascular disease, alzheimer’s disease, hereditary angio-edema, sepsis, inflammation and psoriasis.
Accumulating evidence indicates that the KLK family is dysregulated in cancer. Notably, KLKs exhibit a differential expression pattern and confer a coordinated pattern of up or down-regulation. Given their distinct expression profile in various malignancies, particularly in endocrine-related carcinomas, the KLK family was shown to represent a rich source of tumour biomarkers. KLK3/PSA has received by far the most attention as a valuable tumour marker for screening, diagnosis, and monitoring of prostate cancer.
Epithelial cancer of the ovary is the most lethal gynecologic malignancy. The relative lack of specific signs and symptoms of this disease, coupled with the lack of reliable screening strategies, contributes to a condition that is diagnosed at advanced stages in most patients, resulting in low overall cure rates.
Most cases (75%) are detected at late stages, when the 5-year survival rates are less than 20%. When ovarian cancer is detected early enough, however, the patient’s prognosis is usually excellent since the 5-year survival rate may exceed 90%. Unfortunately, there is no recognized model for ovarian cancer screening, nor any clinical test approved for early-stage diagnosis.
The current ovarian cancer biomarkers have high sensitivity for clinically diagnosed disease. CA125 is by far the most documented and best-performing single biological marker for ovarian cancer. It is the only marker clinically approved for monitoring of ovarian cancer progression and treatment response. CA125, however, has very low sensitivity for early-stage disease, only 50% of women with stage I disease will have elevations in CA 125.
Because of the complexity and heterogeneity of ovarian cancer, it is unlikely that a single biomarker will be able to detect all subtypes and stages of the disease with a high specificity and a high sensitivity. The use of a combination of many biomarker candidates may provide greater potential for early detection of ovarian cancer.
Accumulating data suggest that many tissue Kallikreins represent promising biomarkers for several cancer types, particularly ovarian carcinoma. To date, several KLK genes are reportedly dysregulated in ovarian cancer as evidenced by numerous studies of altered KLK transcript and KLK protein levels in the tumor tissues, cell lines, ascitic fluid, and/or serum of patients with this malignancy.
Serum human kallikrein 6 (KLK6) represents a novel biomarker for ovarian carcinoma. This biomarker is more specific for ovarian cancer than CA-125 because elevations were not seen in benign diseases.
Found that KLK6 can increase the sensitivity of CA-125 at all stages of the disease, including stage I or II disease. Thus, CA-125 and KLK6 could be used in combination to increase the diagnostic sensitivity of each of the biomarkers alone.Similar to CA-125, KLK6 is more frequently elevated in serous ovarian carcinoma than in endometrioid and mucinous carcinoma.
Serum KLK6 is also more frequently elevated in late-stage and higher-grade disease. Accordingly, serum hK6 is a powerful prognostic indicator of patient outcome.
Human kallikrein 10 (KLK10) is another kallikrein that is an unfavorable ovarian cancer prognostic/predictive biomarker. High concentrations of KLK10 were significantly associated with serous histotype, advanced stage, and large residual tumor size. Other data indicate that for stage III and IV patients, hK10 was an independent indicator of reduced overall and progression-free survival.
Studies have shown that Kallikreins 4, 5, 7, 14 &15 are markers of advanced stage diseases, poorly differentiated tumours (grade III & IV) and unfavorable prognosis.
On the other hand, studies of human kallikreins 8, 9, 13 and 14 expression have found them to be independent indicators of early stage disease, lower-grade tumors, no residual tumor, and optimal debulking success, therefore, favorable prognostic indicators.
In the future, it may be worth while to include human kallikreins in a panel for diagnosis and prognosis of ovarian malignancy, since they are highly suited for such multiparametric analysis.