Salivary Kallikrein (Salivary KLK1) as a Diagnostic and Prognostic Biomarkers for Tumors distant from the Oral Cavity.
Some thirty years ago,  I and colleagues at the University of North Carolina at Chapel Hill observed that glandular kallikrein (tissue kallikrein, KLK1) activity was elevated in saliva obtained from oncology patients (1).  We subsequently established that we were measuring glandular kallikrein and not an artifact(2).   This study included the validation of the assay based on p-nitroanilide hydrolysis with kinin release from kininogen as measured by immunoassay.  Other work from our laboratory evaluated other possible confounding issues (3-5).  Suffice to say, we have no reason to doubt the validity of our assay.  In studies which were not published, salivary kallikrein appeared to have value as a prognostic tool in the treatment of colon cancer.   However, this work was not carried forward as (1) we were unable to get a diagnostic company interested in the project nor were we able to secure continuing funding.  Further work was also complicated by the principals moving onto to onto other interests.

There is an earlier post on this subject.  Subsequent to our work, there were two studies reporting increased levels of glandular kallikrein in human saliva. Rosatelli and coworkers (6) observed an increase of kallikrein in saliva in pemphigus foliaceus. Dellalibera and coworkers (7) reported an increase level of kallikrein in saliva in thromboangiilit obliterans.  It was suggested in one study (6) that the increase of glandular kallikrein in saliva was due to systemic inflammation.
Our last paper on this subject was published in 1992 and since that time, interest in kallikrein has greatly increased.  Specifically, there has been a large body of work on kallikrein-like peptidases (KLKs) which includes glandular (tissue) kallikrein as KLK1(8).  As last count, there are 15 kallikrein-like peptidases (9).  Further diversity in kallikrein-related peptidases is accomplished through alternative spicing (10) resulting a large number of isoforms (11).  The expression of such isoforms may have importance in tumor development (12-14) and have potential as predictive and prognostic biomarkers (15,16).   This work does not explain the increased expression of KLK1 in saliva from individuals with tumors distant from the oral cavity nor does the use of molecular medicine for the evaluation of susceptibility, prognostic, or predictive biomarkers preclude to the use of salivary kallikrein as biomarker for cancer.  It is acknowledged that a considerable amount of work would be required to document the positive predictive value (17).

 

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.W., Coffer, J.C., Heizer, W.D, et al., The assay of glandular kallikrein and prekallikrein in human mixed saliva, Arch.Oral.Biol. 33, 641-644, 1988.
3. 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.
4.  Jenzano, J.W., Brown, C.K., and Mauriello, S.M., Temporal variations of glandular kallikrein, protein and amylase in mixed human saliva, Arch.Oral Biol. 32, 757-759, 1987.
5.  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.
6.  Rosatelli, T.B., Roselino, A.M., Dellalibera-Jovillano, R. et al., Increased activity of plasma and tissue kallikreins, plasma kininase II and salivary kallikrein in pemphigus foliasceus (fogo selvagem), Brit.J.Dermatol. 152, 650-657, 2005.
7.  Dellalibera-Joviallano, R., Jovillano, E.E., and Évora, P.R.B., Determination of kininogens levels and kallikrein/kinase II activities in patients with thromboangiitis obliterans, Scand.J.Immunol. 72, 128-133, 2010.
8.  Lundwall, A., Clauss, A., and Olsson, A.Y., Evolution of kallikrein-related peptidases in mammals and identification of a genetic locus encoding potential regulatory inhibitors, Biol.Chem. 387, 243-249, 2006.
9.  Lundwall, A., Band, V., Blaber, M., et al., A comprehensive nomenclature for serine proteases with homology to tissue kallikreins, Biol.Chem. 387, 637-641, 2006.
10.  Irimia, M. and Blencowe, B.J., Alternative splicing: decoding an expansive regulatory layer, Curr.Opin.Cell Biol. 24, 323-332, 2012.
11.  Mitsui, S., Nakamura, T., Okui, A., et al., Multiple promoters regulate tissue-specific alternative splicing of the human kallirein gene, KLK11/hippostatin, FEBS J. 273, 3678-3686, 2006.
12.  Tan, O.L., Whitbread, A.K., Clements, J.S., and Dong, Y., Kallikrein-related peptidase (KLK) family mRNA variants and protein isoforms in hormone-related cancers: do they have a function?, Biol.Chem. 387, 697-705, 2006.
13.  Planque, C., Choi, Y.H., Guyetant, S., et al., Alternative splicing variant of kallikrein-related peptidase 9 as an independent predictor of lung cancer, Clin.Chem. 56, 987-997, 2010.
14.  Talieri, M., Devetzi, M., Scorilas, A., et al., Human kallikrein-related peptidase 12 (KLK12) spice variants expression in breast cancer and their clinical impact, Tumour Biol. 33, 1075-1084, 2012.
15.  Batra, J., Nagle, C.M., O'Mara,T., et al., A kallikrein 15 (KLK15) single nucleotide polymorphism located close to a novel exon shows evidence of association with poor ovarian cancer survival, BMC Cancer 11:119, 2011.
16.  Devatzi, M., Transgas, T., Scorilas, A., et al., Parallel overexpression and clinical significance of kallikren-related peptidases 7 and 14 (KLK7KLK14) in color cancer, Thromb.Haemost. 109, 716-725 2013.
17.  Higgins, M.F., Macken, A.P., Cullen, W., et al., What is the difference between sensitivity and specificity? Or positive predictive value and negative predictive value? And what's a ROC if it's not a type of bird, Ir.Med.J. 106(2 Suppl), 11-13, 2013.