Salivary Kallikrein and Cancer Detection
There are three categories of diagnostic analytes (biomarkers) in the treatment of disease:
The utility of salivary kallikrein as an analyte for the diagnosis and prognosis of cancer has been largely overlooked since studies several decades ago at the University of North Carolina at Chapel Hill(1-3). It is encouraging to see that there has been some recent interest in these studies(4). Saliva is easily obtained from most subjects in a non-invasive approach. The assay is based on the hydrolysis of a peptide nitroanilide substrate and could be easily adapted to simple end-point assay. While the specificity and sensitivity of salivary kallikrein has not been established, a positive test could be used to justify a second, more rigorous evaluation. In work that was not published, data was obtained to suggest that salivary kallikrein has a prognostic value as well. While salivary kallikrein levels did not guide therapeutic choice, successful therapy resulted in a decrease in salivary kallikrein while continued elevation suggested an unsatisfactory clinical outcome. A mechanism for the elevation of salivary kallikrein in cancer was never established. However, it seemed likely that parotid saliva was the source. Kallikrein has been demonstrated in parotid secretion(5-7) and is well documented in pancreas(8-10) which can be considered homologous to parotid.
Early work with the carcinoid syndrome suggested an involvement of kallikrein in metastatic disease(11). More recent work has demonstrated the involvement of glandular (tissue) kallikrein with cancer(12-19). It is not clear as to the role, if any, of glandular kallikrein in metastatic disease. Glandular kallikrein has been suggested to have a role in the processing of peptide growth factors such as EGF(20) and thus could have an autocrine or paracine role in tumor development. It is also possible that the glandular kallikrein activity is a non-specific part of the inflammatory response associated with tumors(21).
The bulk of the evidence suggests that the assay of kallikrein in saliva could be useful in screening for malignant disease. As indicated above, it is not clear as to the mechanism by which salivary kallikrein levels are elevated. In studies which were not published, salivary kallikrein appeared to used as a prognostic tool in the treatment of colon cancer. It is noted that most of the investigators involved in this project have moved onto other interests.
References
1 Jenzano, J.W., Courts, N.F., Timko, D.A., and Lundblad, R.L., Levels of glandular kallikrein in whole saliva obtained from patients with solid tumors remote from the oral cavity, J.Dent.Res. 65, 67-70, 1986
2. Jenzano, J.F, Daniel, P.A., Kent, R.T., et al., Evaluation of kallikrein in human-parotid and submandibular saliva, Archs.Oral Biol. 31, 627-628, 1986
3. Jenzano, J.F., Hogan, S.L., and Lundblad, R.L., The influence of age, sex and race on salivary kallikrein levels in human mixed saliva, Agents Actions 35, 29-33, 1992
4. Streckfus, C.F., Bigler, L.R., and Zwick, M., The use of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to detect putative breast cancer markers in saliva: a feasibility study, J.Oral Pathol.Med. 35. 292-300, 2006
5. Orstavik, T.B., Brandtzaeg, P., Nustad, K., and Pierce, J.V., Immunohistochemical localization of kallikrein in human pancreas and salivary glands, J.Histochem.Cytochem. 28, 557-562, 1980
6. Kimura, K. and Moriya, H., Enzyme- and immuno-histochemical localization of kallikrein. I. The human parotid gland, Histochemistry 80, 367-372, 1984
7. Beeley, J.A. and Khoo, K.S., Salivary proteins in rheumatoid arthritis and Sjogren’s syndrome: one-dimensional and two-dimensional electrophoretic studies, Electrophoresis 20, 1652-1660, 1999
8. Fiedler, F. and Leysath, G., Substrate specificity of porcine pancreatic kallikrein, Ann.Exp.Med.Biol. 120A, 261-271, 1979
9. Amouric, M. and Figarella, C., Some properties of human pancreatic kallikrein and comparison with human trypsins and porcine kallikrein, Hoppe Seylers Z.Physiol.Chem. 361, 85-90, 1980
10. Ole-Moiyoi, O.K., Pinkus, G.S, Spragg, J., and Austen, K.F., On localization of kallikrein in the human pancreas and salivary glands by direct immunofluorescence, J.Histochem.Cytochem. 28, 1359, 1980
11. Mason, D.T. and Melmon, K.L., New understanding of the mechanism of the carcinoid flush, Ann.Int.Med. 65, 1334-1339, 1966
12. Yousef, G.M. and Diamandis, E.P., An overview on the kallikrein gene families in human other species: emerging candidate tumour markers, Clin.Biochem. 36, 443-452, 2003
13. Clements, J.A., Willemsen, N.M., Myers, S.A., and Dong, Y., The tissue kallikrein family of serine proteases: functional roles in human disease and potential as clinical biomarkers, Crit.Rev.Clin.Lab.Sci. 41, 265-12, 2004
14. Yousef, G.M., Obiezu, C.V., Luo, L.Y., et al., Human tissue kallikreins: from gene structure to function and clinical applications, Adv.Clin.Chem. 39, 11-79, 2005
15. Diamini, E. and Bhoola, K.D, Upregulation of tissue kallikrein, kinin B1 receptor, kinin B2 receptor in mast and giant cells infiltrating squamous cell carcinoma, J.Clin.Pathol. 58, 915-922, 2005
16. Paliouras, M. and Diamandis, E.P., The kallikrein world: an update on the human tissue kallikreins, Biol.Chem. 387, 643-652, 2006
17. Schmidtt, M. and Magdolen, V., Using kallikrein-related peptidases (KLK) as novel cancer biomarkers, Thromb.Haemost. 101, 222-224, 2009
18. Thomadaki, H., Mavridis, K., Talieri, M., and Scorilas, A., Treatment of PC3 prostate cancer cells with mitooxantrone, etoposide, doxorubicin and carboplatin induced distinct alterations in the expression of kallikreins 5 and 11, Thromb.Haemost. 101, 373-380, 2009
19. Papachristopoulou, G., Avgeris, M., and Scorilas, A., Expression analysis and study of KLK4 in benign and malignant breast tumors, Thromb.Haemost. 101, 381-387, 2009
20. Casalino-Matsuda, S.M., Monzon, M.E., Conner, G.E., et al., Role of hyaluronan and reactive oxygen species in tissue kallikrein-mediated epidermal growth factor receptor activation in human airways, J.Biol.Chem. 279, 21606-21616, 2004
21. Campbell, D.J., The kallikrein-kinin system in humans, Clin.Exp.Pharmacol.Physiol. 28, 1060-1065, 2001