Telomerase and Hepsin as prognostic factors in prostate cancer progression and metastasis Ileana...

Telomerase and Hepsin as Telomerase and Hepsin as prognostic factors in prognostic factors in

prostate cancer progression prostate cancer progression and metastasisand metastasis

Ileana Constantinescu*, Rodica Tudor***Ileana Constantinescu*, Rodica Tudor*** M.Harza**, M.Manu**, G.Gluck** and I. Sinescu**M.Harza**, M.Manu**, G.Gluck** and I. Sinescu**

Centre for Immunogenetics and Virology*Centre for Immunogenetics and Virology*Centre of Urology, Dialysis, Nephrology and Kidney Transplantation**Centre of Urology, Dialysis, Nephrology and Kidney Transplantation**

Fundeni Clinical InstituteFundeni Clinical InstituteBatistei Medical Centre***Batistei Medical Centre***

Fundeni Centre for Immunogenetics & Virology

Pecorino L. Molecular Biology of Cancer, Mechanisms, Targets, and Therapeutics 2005, 1: 3, Oxford University Press.


The six hallmarks of cancerThe six hallmarks of cancer

Unlimited replicative potentialUnlimited replicative potential

Altered regulation of telomere maintenance Altered regulation of telomere maintenance results in unlimited replicative potentialresults in unlimited replicative potential

Angiogenesis (formation of new blood vessels)Angiogenesis (formation of new blood vessels)

Invasion and metastasisInvasion and metastasis

The movement of cancer cells to other parts of The movement of cancer cells to other parts of the body is a major cause of cancer deathsthe body is a major cause of cancer deaths

Mutations alter the activity of enzymes Mutations alter the activity of enzymes involved in invasion and alter molecules involved in invasion and alter molecules involved in cell-cell and cetlextracellular involved in cell-cell and cetlextracellular adhesionadhesion



IntroductionIntroduction Prostate cancer is the most common male malignancy and the Prostate cancer is the most common male malignancy and the

second leading cause of male cancer death; therefore is a great second leading cause of male cancer death; therefore is a great demand for noninvasive assay for early detection of prostate cancer.demand for noninvasive assay for early detection of prostate cancer.

Working prostate tumor samples is very dificult because the Working prostate tumor samples is very dificult because the malignancy is heterougenous and multifocal and early-stage tumors malignancy is heterougenous and multifocal and early-stage tumors are nonpalpable. are nonpalpable.

On the contrary, exfoliated cells representthe cancer status of the On the contrary, exfoliated cells representthe cancer status of the entire gland better due to the general tendency of cancer cells to entire gland better due to the general tendency of cancer cells to exfoliate into biological fluids.exfoliate into biological fluids.

One of the aim of this research is to clarify whether quantitative One of the aim of this research is to clarify whether quantitative analysis of telomerase activity in exfoliated cells in urine could serve analysis of telomerase activity in exfoliated cells in urine could serve as a reliable molecular marker of prostate malignancy. The second as a reliable molecular marker of prostate malignancy. The second aspect of interest is that prostate cancer related deaths are aspect of interest is that prostate cancer related deaths are associated with metastasis. However, little is known about the associated with metastasis. However, little is known about the mechanisms of this process.mechanisms of this process.

Hepsin is a cell surface serine protease that is markedly upregulated Hepsin is a cell surface serine protease that is markedly upregulated in human prostate cancer; however, the functional significance of this in human prostate cancer; however, the functional significance of this upregulationis unknown. upregulationis unknown.

There are scientific evidence that hepsin overexpression in prostate There are scientific evidence that hepsin overexpression in prostate epithelium in vivo causes disorganization of the basement epithelium in vivo causes disorganization of the basement membrane.membrane.


Botchkina G.I, Kim R.H, Botchkina I.L, Kirshenbaum A, Frisher Z, Adler H.L Noninvasive Detection of Prostate Cancer by Quantitative Analysis of Telomerase Activity, Clin Cancer Res, 2005;11 (9) 1.

Gene structure



Types of mutation



Material and MethodsMaterial and Methods

WeWe have selected 58 patients with biopsy proven have selected 58 patients with biopsy proven prostate cancer (N=38), with elevated total PSA prostate cancer (N=38), with elevated total PSA levels and also with normal PSA levels. We have levels and also with normal PSA levels. We have also included patients with PBH (N=20).There also included patients with PBH (N=20).There were included patients with (N=8) and without were included patients with (N=8) and without metastatsis (N=30).metastatsis (N=30).

For the assessment of PSA we have used For the assessment of PSA we have used Microparticle Enzyme ImmunoAssay (MEIA) Microparticle Enzyme ImmunoAssay (MEIA) AxSym, ABBOTT. Telomerase was worked by PCR AxSym, ABBOTT. Telomerase was worked by PCR and Hepsin by real time PCR. Quantitative ELISA and Hepsin by real time PCR. Quantitative ELISA was used for the measurement of serum was used for the measurement of serum neopterin.neopterin.


ResultsResults In all patients with elevated total PSA levels both In all patients with elevated total PSA levels both

telomerase and hepsin genes over expression were telomerase and hepsin genes over expression were found. These values were directly correlated with found. These values were directly correlated with significantly high serum of neopterin levels.significantly high serum of neopterin levels.

In some patients with normal PSA levels we have noticed In some patients with normal PSA levels we have noticed significantly raised telomerase gene expression.significantly raised telomerase gene expression.

In some patients with normal PSA neopterin levels were In some patients with normal PSA neopterin levels were normal.normal.

In patients with metastasis hepsin gene overexpression In patients with metastasis hepsin gene overexpression was noticed. A small percentage of patients without was noticed. A small percentage of patients without metastasis had hepsin overexpression as well.metastasis had hepsin overexpression as well.


HighTelomerase Activity (TA)

100%

Prostate Cancer


N=38

N=20 BPH

No Telomerase Activity 73 %

Low TA15%High TA

12%



N=38 patients with metastasis

21,1% 78,9%100% high

hepsin activity

patients with metastasis metastasis free patients


N=30 metastasis free patients

83%17%

Hepsin low gene expresion Hepsin high gene expresion

ConclusionsConclusions

Telomerase and hepsinTelomerase and hepsin are useful are useful noninvasive markers for complete noninvasive markers for complete assessment of prostate cancer. assessment of prostate cancer.

Telomerase gene expressionTelomerase gene expression is useful for is useful for both early detection and diagnostic of both early detection and diagnostic of prostate cancer.prostate cancer.

HepsinHepsin is valuable for early detection of is valuable for early detection of metastatic invasion in prostate cancer.metastatic invasion in prostate cancer.

Also, Also, both markersboth markers are very useful as are very useful as monitoring tools of anti cancer therapy in monitoring tools of anti cancer therapy in these patients.these patients.


Telomerase and Hepsin as prognostic factors in prostate cancer progression and metastasis Ileana...

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