RUOLO RUOLO DELL’INFIAMMAZIONE E DELL’INFIAMMAZIONE E

CARCINOMA PROSTATICOCARCINOMA PROSTATICO

Luca CindoloLuca Cindolo

The evidence that link cancer and inflammation

Inflammatory disease increases the risk of cancer (e.g. thyroid, bladder, cervical, ovarian, oesophageal, gastric, intestinal)

Non-steroidal inflammatory drugs protect against some cancers (e.g. colon and breast)

Inflammatory leucocytes, cytokines and chemokines are present in all (?) experimental and human cancers from the earliest stages

Inflammatory pathways are downstream of oncogenic mutations (e.g. ras, myc, RET/PTC)

Targeting cytokines, chemokines, key transcription factors of inflammation and inflammatory cells, decreases incidence and spread of cancer (e.g. TNF-α, IL-1β, NF-κB, Stats)

Infections and human cancers*IARC Group 1 Carcinogens: “…the agent (mixture) is carcinogenic to humans…”

10 of 64 Group 1 Carcinogens are infectious agents

Epstein-Barr virusHelicobacter pylori (infection with)

Hepatitis B virus (chronic infection with)Hepatitis C virus (chronic infection with)

Human immunodeficiency virus type 1 (infection with)Human papillomavirus type 16Human papillomavirus type 18

Human T-cell lymphotropic virus type IOpisthorchis viverrini (infection with)

Schistosoma haematobium (infection with)

*World Health Organization International Agency for Research on Cancer (IARC); see www.iarc.fr

Infections and cancers

Klein EA, et al. Curr Opin Urol 2008,18:315–319

NORMALNORMAL CANCERCANCER

NORMALNORMAL HYPERPLASIAHYPERPLASIA IN IN SITUSITU CANCERCANCER INVASIVE INVASIVE CANCERCANCER

PRECANCERPRECANCER

ABNORMALITYABNORMALITYNORMALITYNORMALITY

DYSPLASIADYSPLASIA

??

????

??

??

Open questionsOpen questions

• What is the border between “Normal” and What is the border between “Normal” and “Abnormal”?“Abnormal”?

• How long does it take for precancer to turn How long does it take for precancer to turn into cancer?into cancer?

• What is the point of no return?What is the point of no return?• Are lesions biologically different in different Are lesions biologically different in different

organs?organs?

Histology is a snapshot of the disease Histology is a snapshot of the disease ……

……while carcinogenesis is a dynamic processwhile carcinogenesis is a dynamic process

Open questionsOpen questions

• What is the border between “Normal” and What is the border between “Normal” and “Abnormal”?“Abnormal”?

• How long does it take for precancer to turn How long does it take for precancer to turn into cancer?into cancer?

• What is the point of no return?What is the point of no return?• Are lesions biologically different in different Are lesions biologically different in different

organs?organs?

Prostate Intraepithelial Neoplasia (PIN)

Prostate epithelial cell hierarchy

Basal layer

De Marzo et al. Nature Rev Cancer 2007

Causes of Causes of prostate prostate

atrophy and atrophy and inflammationinflammation

A genetic susceptibility to develop viral/bacterial infections or the inability to counter physical/chemical injuries may :

• produce an irreversible cell damage

• cause loss of tolerance to normal prostate antigens and induce an autoimmune self-perpetuating reaction

• create a “field effect” for the development of CaP

Nelson WG et al. NEJM 2003;349:366-381

The interest for inflammatory/atrophic lesions in prostate The interest for inflammatory/atrophic lesions in prostate cancer grew in the 90’s based on prior observations in cancer grew in the 90’s based on prior observations in other organs such as stomach, liver and large bowelother organs such as stomach, liver and large bowel

De Marzo et al. Nature Rev Cancer 2007

Steps to prostate cancer through Steps to prostate cancer through inflammation/atrophy #1inflammation/atrophy #1

• Injury of the luminal cell layer (any kind)• Reactive (defensive) hyperplasia of basal and secretory cells (PIA/PAH) with

initiation of genetic instability• Cytokines released by the inflammatory cells slowly induce epithelial

proliferation and angiogenesis• Continued proliferation of genetically unstable cells leads to accumulation of

genomic changes and to neoplastic transformation through PIN

Steps to prostate cancer through Steps to prostate cancer through inflammation/atrophy #2inflammation/atrophy #2

Klein EA, et al. Curr Opin Urol 2008,18:315–319

Inflammation and atrophy Inflammation and atrophy as risk factors for CaPas risk factors for CaP

PROsPROs• Epidemiological studies on Epidemiological studies on

environmental exposures; viral/bacterial environmental exposures; viral/bacterial infections ; chemoprevention trials with infections ; chemoprevention trials with NSAIDsNSAIDs

• Morphologic transition between PAH Morphologic transition between PAH and PINand PIN

• PAH and CaP share the down-regulation PAH and CaP share the down-regulation of known tumor suppressor genes of known tumor suppressor genes ((NKX3.1NKX3.1, , CDKN1B, PTEN), CDKN1B, PTEN), care-taker care-taker genesgenes genes genes (GSTP1), (GSTP1), genes with anti-genes with anti-viral (viral (RNASEL) orRNASEL) or anti-bacterial functions anti-bacterial functions (MSR1)(MSR1)

• No highly penetrant hereditary prostate No highly penetrant hereditary prostate cancer genes have been discovered so cancer genes have been discovered so farfar

CONsCONs• No strong evidence of the prostate No strong evidence of the prostate

inflammatory “field effect “ in animal inflammatory “field effect “ in animal modelsmodels

• PAH lesions are not clonalPAH lesions are not clonal• The causes of prostate inflammation The causes of prostate inflammation

are extremely variableare extremely variable• The target cell type of the The target cell type of the

inflammatory damage is not definedinflammatory damage is not defined• Inflammatory lesions of the prostate Inflammatory lesions of the prostate

are more common than CaPare more common than CaP• The “inflammatory” hypothesis for The “inflammatory” hypothesis for

CaP has not been widely accepted CaP has not been widely accepted among scientistsamong scientists

No systematic classification of atrophic and No systematic classification of atrophic and inflammatory lesions of the prostate was done inflammatory lesions of the prostate was done

before 2006before 2006

Common features of atrophic lesionsCommon features of atrophic lesions

• The epithelium is composed of two layers consisting of basal The epithelium is composed of two layers consisting of basal cells and luminal cellscells and luminal cells

• Luminal cells are nearly flat with extremely scant cytoplasm Luminal cells are nearly flat with extremely scant cytoplasm and sometimes dark appearance at low magnification. and sometimes dark appearance at low magnification.

• The two layers may be difficult to discriminate by standard The two layers may be difficult to discriminate by standard H&E staining. H&E staining.

• The basal layer can be demonstrated by staining against The basal layer can be demonstrated by staining against basal cell specific cytokeratins (5/6, 34basal cell specific cytokeratins (5/6, 3412) or p63.12) or p63.

• The terms PIA and PAH overlap with the latter retaining a The terms PIA and PAH overlap with the latter retaining a more biological meaning.more biological meaning.

• PAH is the only atrophic lesion correlated to the PAH is the only atrophic lesion correlated to the development of CaPdevelopment of CaP

Atrophy/PAH/PINAtrophy/PAH/PIN

NORMALNORMAL CANCERCANCER

NORMALNORMAL HYPERPLASIAHYPERPLASIA IN IN SITUSITU CANCERCANCER INVASIVE INVASIVE CANCERCANCER

PRECANCERPRECANCER

ABNORMALITYABNORMALITYNORMALITYNORMALITY

DYSPLASIADYSPLASIA

??PINPININFLAMMATIONINFLAMMATION

ATROPHYATROPHYPAHPAH

Relationship between age, metabolic syndrome, inflammation, hormonal alterations, and benign prostatic hyperplasia (BPH).

Briganti A, et al. Eur Urol Suppl 2009;13:865-871

Platinum Slide Series

CANCER

From well-adapted to starvation and fighting infection to poorly adapted to overnutrition and excess inflammation

Schematic diagram showing some of the Serenoa repens extract (SrE) targets at the level of the prostate cell.DHT = dihydrotestosterone; EGF = epidermal growth factor; FGF = fibroblast growth factor.

Fouad K. Habib Eur Urol Suppl 2009;13:887-893

Platinum Slide Series

Post-Atrophic HyperplasiaPost-Atrophic Hyperplasia• Acini of PAH are smalland Acini of PAH are smalland

arranged in a lobular distribution arranged in a lobular distribution around a dilated ‘‘feeder’’ duct, around a dilated ‘‘feeder’’ duct, similarly to breast lobulessimilarly to breast lobules

• The number of acini per unit area The number of acini per unit area is increased compared to the is increased compared to the normal epithelium but It’s normal epithelium but It’s debated if there is actual debated if there is actual “hyperplasia”“hyperplasia”

• Possible moderate nucleolar Possible moderate nucleolar enlargement can lead to enlargement can lead to diagnostic confusion with CaPdiagnostic confusion with CaP

• Most of the lesions contain at Most of the lesions contain at least some chronic (rarely acute) least some chronic (rarely acute) inflammatory cellsinflammatory cells

• This is the only lesion that has This is the only lesion that has been related to CaPbeen related to CaP