BERKELEY, CA (UroToday.com) - Reviews on the structure and properties of carboxypeptidase M (CPM) often start with its discovery as a “basic carboxypeptidase activity” in urine. The activity present in urine comes from a shedded form of CPM, which originally was attached to the outer plasma membrane by a GPI-anchor. The presence of CPM on Madin-Darby canine kidney cells (a cell line derived from distal tubular epithelial cells) supported the growing notion that the kidney is a rich source of CPM. We now know that the expression levels of CPM in the kidney are not particularly high. In fact, its expression is mostly restricted to epithelial cells of the tubules and collecting ducts of the nephrons. CPM immunoreactivity is present in the lumen, on the (apical) cell surface and in some instances also intracellular. Based on this observation, a role of CPM in amino acid salvage appears plausible. The catalytic activity of CPM is very restricted. It only removes C-terminal lysines and arginines from peptides. A number of highly active peptides end with arginine or lysine: bradykinin, anaphyllatoxins, defensins, specific chemokines and epidermal growth factor. Their biological activity is abrogated or modified by the action of CPM. One can speculate that a different role of CPM in the kidney relates to the biological activity of its substrates.
Independently, the carboxypeptidase M gene was discovered on chromosome 12q15, belonging to a group of genes associated with the pathogenesis of solid tumors. This chromosome region contains a number of known oncogenes and genes involved in cell cycle control, differentiation, and cytokine biology. Moreover it is an unstable region and many aberrations have been described in 12q13-15. Amplification of CPM, together with the oncogene marker MDM2, has been observed in specific classes of tumors. There has also been a report of CPM as a fusion partner in chromosome 12 translocations. Increased CPM expression was found to be a useful marker to discriminate well-differentiated liposarcoma from lipomas. Combination of high expression of CPM and EGFR (epidermal growth factor receptor) was described as a prognostic marker for poor outcome in clear-cell lung carcinoma. We investigated the presence of CPM and EGFR in different types of renal cell carcinoma and found that, with the exception of papillary renal cell carcinoma, CPM expression was lost as a result of dedifferentiation of the cancer cells. Nevertheless, CPM is present in the tumor environment as it appears on newly formed vasculature and on tumor associated macrophages.
CPM has been linked to inflammation many years ago when it was - yet again - discovered as a macrophage differentiation antigen. It is not known whether CPM plays a crucial role in macrophage biology. There is some debate whether tumor-associated inflammation promotes or reduces tumorigenesis, growth, and migration. What is clear, however, is that CPM is there, and it is suitable for pharmacological intervention. A number of theoretical CPM substrates have, themselves, been investigated as anticancer drug targets: bradykinin, anaphyllatoxin C5a, chemokine CXCL12. The presence of CPM in the tumor environment opens up new research perspectives.
- Skidgel RA, Davis RM, Erdos EG. Purification of a human urinary carboxypeptidase (kininase) distinct from carboxypeptidases A, B, or N. Anal Biochem 1984;140(2):520-31.
- McGwire GB, Becker RP, Skidgel RA. Carboxypeptidase M, a glycosylphosphatidylinositol-anchored protein, is localized on both the apical and basolateral domains of polarized Madin-Darby canine kidney cells. J Biol Chem 1999;274(44):31632-40.
- Denis CJ, Deiteren K, Hendriks D, Proost P, Lambeir AM. Carboxypeptidase M in apoptosis, adipogenesis and cancer. Clin Chim Acta 2012;415C:306-316.
- Kas K, Schoenmakers EF, Van de Ven WJ. Physical map location of the human carboxypeptidase M gene (CPM) distal to D12S375 and proximal to D12S8 at chromosome 12q15. Genomics 1995;30:403-5.
- Mejia-Guerrero S, Quejada M, Gokgoz N, Gill M, Parkes RK, Wunder JS, et al. Characterization of the 12q15 MDM2 and 12q13-14 CDK4 amplicons and clinical correlations in osteosarcoma. Genes Chromosomes Cancer 2010;49:518-25.
- Hahn Y, Bera TK, Gehlhaus K, Kirsch IR, Pastan IH, Lee B. Finding fusion genes resulting from chromosome rearrangement by analyzing the expressed sequence databases. Proc Natl Acad Sci U S A 2004;101:13257-61.
- Zhang H, Erickson-Johnson M, Wang X, Oliveira JL, Nascimento AG, Sim FH, et al. Molecular testing for lipomatous tumors: critical analysis and test recommendations based on the analysis of 405 extremity-based tumors. Am J Surg Pathol 2010;34:1304-11.
- sakiris I, Soos G, Nemes Z, Kiss SS, Andras C, Szanto J, et al. The presence of carboxypeptidase-M in tumour cells signifies epidermal growth factor receptor expression in lung adenocarcinomas: the coexistence predicts a poor prognosis regardless of EGFR levels. J Cancer Res Clin Oncol 2008;134:439-51.
- Rehli M, Krause SW, Kreutz M, Andreesen R. Carboxypeptidase M is identical to the MAX.1 antigen and its expression is associated with monocyte to macrophage differentiation. J Biol Chem 1995;270:15644-9.
- Denis CJ, Lambeir AM. The potential of carboxypeptidase M as a therapeutic target in cancer. Expert Opin Ther Targets. 2013;17(3):265-79.
Anne-Marie Lambeir as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
University of Antwerp, Laboratory of Medical Biochemistry, Universiteitsplein 1—Building S, Room 5.15, B-2610, Antwerp, Belgium. E-mail:
Mapping of carboxypeptidase M in normal human kidney and renal cell carcinoma: Expression in tumor-associated neovasculature and macrophages - Abstract
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