Inflammation and Prostate Diseases Progression

Alessandro SciarraChairman Prostate UnitPoliclinico Umberto IUniversity La Sapienza - Rome, Italy

BPH: long period before clinical evidence

Normal LGPIN HGPIN Carcinoma

10-20 years 1-10 years

Prostate Cancer: long period before clinical evidence

Question 1 ?

May inflammation significantly condition the development and future

progression of prostate diseases ?

Question 2 ?

May inflammation be considered a risk factor so to be integrated

in risk stratification analysesfor prostate diseases ?

Association infiammation – prostatic diseases

Evidences: • Epidemiologic

• Genetic

• Mechanism of action

• Histologic

• Clinical

5 years Follow-up

In the group with CI at 1° biopsy, 20% of pts developed PC and 6% HPIN

In the group without CI at 1° biopsy , 6% of pts developed PC. P<0.05

Association between inflammation and BPH

Urology 71: 475-479, 2008. ©2008 Elsevier

Association infiammation – prostatic diseases

Evidences:

• Epidemiologic

• Genetic

• Mechanism of action

• Histologic

• Clinical

Association infiammation – prostatic diseases

Evidences:

• Epidemiologic

• Genetic

• Mechanism of action

• Histologic

• Clinical

Inflammation and BPH

Linfocita

Macrofago

Neutrofilo

Citochine

Radicali ossigeno

Cytokines and inflammation in the prostate

Kramer et al, Eur Urol, 2007; 51:1202-16

Inflammation: possible pathogenesis

repeated tissue damage excessive production of oxidative damages post-translational DNA modifications increased cell proliferation and angiogenesis

Inflammation:two possible actorsNOS and COX

Increased apoptosis (TUNEL) with rofecoxib

The role of inflammation in the human prostate

Lucia et al, Curr Urol Rep, 2008; 9:272-78

Modification epithelial function

Tissue damage

Modification stromal function

Infiammation Angiogenesis

Epithelial hyperplasia

Stromal hyperplasia

FGFsIGFs

TGF-Cyr61

Citochine

FGFsIGFs

TGF-Cyr61

Citochine

Diseases Progression

↑ IL-8 ↓ PDF

↑ IL-8

Inflammation can stimulate prostatic disease progression

Which inflammation induces prostatic progression?

Evidences: • Histological data – PSA

• Clinical data

Histopathological aspects of BPH

Inflammatory aspectsHistological aggressiveness

• 0 = no contact between inflammatory cells and glandular epithelium• 1 = contact between inflammation and epithelium• 2 = interstitial infiltrate with glandular disruption• 3 = glandular disruption on more than 25%

Irani; J Urol 1997

Infiammation: precancerous prostatic lesions

Prostata infiammata

PIA(proliferative

inflammatory atrophy)

PIN(prostatic

intraepithelial neoplasia)

CARCINOMA

Inflammation: potential precursor lesions ?

Which inflammation induces prostatic progression?

Evidences:

• Histological data – PSA

• Clinical data:- Frequency of the process- Association with progression

Delongchamps et al, J Urol 2008, 179:1736-40

• Prospective analysis on 167 prostate during autopsy.

• Pathologic analysis identified all carcinoma focus, BPH nodule and acute or chronic inflammation area.

• The prevalence of the association between carcinoma, BPH and infiammation, has been evaluated.

Inflammation and BPH

Delongchamps et al, J Urol 2008, 179:1736-40

In BPH areas ,75% were associated with chronic inflammation (p= 0.01).

67.6%

32.4%

Infiammation and BPH

Delongchamps et al, J Urol 2008, 179:1736-40

Distribution of infiammation Inflammation association with age

CONCLUSIONs: Chronic inflammation was commonly found during autopsies. Inflammation was directly associated with BPH

A. Sciarra et al. Eur Urol 2000

Inflammation and prostate volume:who influences the other ?

A. Sciarra et al. Eur Urol 2000

50

40

30

20

10

030-39 40-49 50-59 60-69 70-79 80-89

cc

acute - trendacute

chronic - trendchronic

Chronic inflammation: F(1,2)=408.64; p=0.002Acute inflammation: F(1,2)=2.292; p=0.269

Inflammation and progression risk: MTOPS

Roehrborn CG,. AUA meeting 2005, Abstract No. 1277

544 patients from MTOPS study with acute (only 31) or chronic inflammation at basal prostate biopsy , compared with cases without infiammation

Patients with inflammation were elderly (64 vs. 62.8 years, p=0.001), with higher volume prostates (41.1 vs. 36.8 ml; p=0.0002) and higher PSA levels (3.3 vs. 2.5 ng/ml; p<0.0001).

In these patients with inflammation a higher risk of acute urinary retention episodes and a positive trend in favour of clinical progression was found (21.0 vs. 13.2%; p=0.083).

Inflammation contributes to BPH progression

Impact of inflammation on BPH progression

C. Roehrborn, 2005. Studio MTOPS

No infiammationInfiammation

Roehrborn C. 2006

Inflammation: risk factor for BPH progression or PC development

Inflammation as precursor of Prostate Cancer:Rationale for Preventive Strategies ?

How to select patients with BPH and inflammation ?

Evidences: • Symtoms

• Imaging

• Markers

How to select patients ?Histology, no very often available

Different stages for prostatic inflammation

No inflammation Low

Moderate Severe

How to select patients ? LUTS and IPSS

Relationship between inflammation and symptoms in BPH

Multiparametric magnetic resonance with spectroscopic analysis: a modern approach in prostatic imaging

Prostate 1H-MRSI (cancer)

Cr:Creatine = it increases in hypermetabolism

Ch:Choline = cellular turnover

Ci:Citrate = terminal metabolites of Krebs cycle

1234

Normal inflammation HGPINLGPC

HGPC

Systemic Markers for infiammation

Shenk et al, Am J Epidemiol, 2010; 171:571-82

Case-control nested study (4971 cases) on the association between

inflammatory markers and symptomatic BPH based on the placebo arm of PCPT

study

IL-8 as marker of inflammation in BPH

Liangren et al, Urology, 2009; 74:340-4

IL-8 levels in prostatic secretion

Sensibility and specificity of IL-8 to identify BPH associated ot inflammation versus BPH alone were85.7% and 91.3% respectively, using a cut-off of 3992 pg/mL

Urinary markers for inflammation

Robert et al, Prostate, 2011, in press

• 90 tissue prostatic samples obtained from BPH patients waiting for surgery

• Urinary samples obtained after digital rectal examination

• Inflammatory score was classified on the basis of inflammatory cells extension:

– 0: no inflammation– 1: mild inflammation– 2: moderate inflammation– 3: severe infiammation

Mean level of genes expression in 90 samples from BPH cases on the basis of inflammation score

Robert G et al Nijmegen med Centre

Possible results from a long term block of prostatic inflammation

• Improvement of LUTS correlated to prostatic inflammation

• Prevention of LUTS progression correlated to prostatic inflammation

• Reduction of the risk of BPH-related complications (AUR)

• Synergic effect with other drugs used to block BPH progression

Which drug for prostatic inflammation - BPH

Evidences: • Experimental

– Studies on primary cultures– Inhibition on inflammatory factors– Effect on proliferation/apoptosis

• Clinical

– Long term therapy– Combination with alpha1 blockers– Combination with 5 ARI

Epitelio prosta

tico tipo 2

Epitelio prosta

tico tipo 1

Fibroblasti prostatici tipo 2

Fibroblasti prostatici ti

po 1

Fibroblasti cutanei tipo 1

Fibroblasti cutanei tipo 2

Fibroblasti della mammella tipo 1

Fibroblasti della mammella tipo 2

Tessuto re

nale tipo 1

Tessuto re

nale tipo 2

Epididimo tipo 1

Epididimo tipo 2

Testicolo tipo1

Testicolo tipo 2

Serenoa Repens exane: specific for prostate tissue

CELL TYPE

% A

POPT

OSI

S

Serenoa Repens exane: Hypothesis for a mechanism of action

Stromal and epithelial human prostate cells

Modification lipid-fatty acid asset (1-5) (Ev Lev 2b)

Reduction 5AR I-II

Increased ratio Apoptosis/proliferation (2,6,7)(Ev Lev 2b)

Mitochondrial Block/distruction(2,4)(Ev Lev 2b)

1-Buck J Urol 20042-Bayne Prostate 1999,J urol 20003-Habib Eur Urol 20094-Petrangeli JCP 20095-Paubert-Braquet Prostglandin 1998976-Vacherot Prostate 20097-Vela Navarrete J Urol 2005

Cellular membrane damage-increased permeab. (nuclear, mitochondrial)(1-5) (Ev Lev 2b)

Effect AR-ER

Chromatin condensation(2,3)(Ev. Lev 4)

inhibition 5 lipoxigenase (5)(Ev Lev 2b)

Reducion ecosanoid prod.= leucotren (5)(Ev Lev 2b)

antii

nfla

mm

ator

y

RESULTS CELL COUNT INFLAMMATORY PATTERNS

Apoptosis-prolifetion NF-KB ANALYSIS

IL-6, CCL-5, COX-2

Which drug for prostatic inflammation - BPH

Evidences:

• Experimental

– Studies on primary cultures– Inhibition on inflammatory factors– Effect on proliferation/apoptosis

• Clinical

– Long term therapy– Combination with alpha1 blockers– Combination with 5 ARI

Increased apoptosis (TUNEL) using the combination of rofecoxib - finasteride

How to treat BPH- inflammation

Modificato da Roehrborn C.G., BJU 2004

Anti-inflammatory on the prostate

Anti-inflammatory on the prostate

Low volumeLow PSA

No treatments

High volumeElevated PSA

5 ARI preventive treatment

Low volume Low PSA

-blocker

High volumeElevated PSA

Combination 5 ARI – alpha blocker

IPSS≤7

LUTS moderate-severeLUTS mild

IPSS>7

Patient

Symptoms or parameters correlated to prostatic inflammation