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RUOLO DELL’INFIAMMAZIONE E CARCINOMA PROSTATICO Luca 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, IL1β, 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 virus Helicobacter 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 16 Human papillomavirus type 18 Human T-cell lymphotropic virus type I Opisthorchis 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 ? ? NORMALITY ABNORMALITY ? ? NORMAL PRECANCER CANCER ? NORMAL HYPERPLASIA DYSPLASIA IN SITU CANCER INVASIVE CANCER Open questions • What is the border between “Normal” and “Abnormal”? • How long does it take for precancer to turn into cancer? • What is the point of no return? • Are lesions biologically different in different organs? Histology is a snapshot of the disease … …while carcinogenesis is a dynamic process Open questions • What is the border between “Normal” and “Abnormal”? • How long does it take for precancer to turn into cancer? • What is the point of no return? • Are lesions biologically different in different organs? Prostate Intraepithelial Neoplasia (PIN) Prostate epithelial cell hierarchy Basal layer Causes of prostate atrophy and inflammation De Marzo et al. Nature Rev Cancer 2007 The interest for inflammatory/atrophic lesions in prostate cancer grew in the 90’s based on prior observations in other organs such as stomach, liver and large bowel 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 Steps to prostate cancer through inflammation/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 De Marzo et al. Nature Rev Cancer 2007 Steps to prostate cancer through inflammation/atrophy #2 Klein EA, et al. Curr Opin Urol 2008,18:315–319 Inflammation and atrophy as risk factors for CaP • • • • PROs Epidemiological studies on environmental exposures; viral/bacterial infections ; chemoprevention trials with NSAIDs Morphologic transition between PAH and PIN PAH and CaP share the down-regulation of known tumor suppressor genes (NKX3.1, CDKN1B, PTEN), care-taker genes genes (GSTP1), genes with antiviral (RNASEL) or anti-bacterial functions (MSR1) No highly penetrant hereditary prostate cancer genes have been discovered so far • • • • • • CONs No strong evidence of the prostate inflammatory “field effect “ in animal models PAH lesions are not clonal The causes of prostate inflammation are extremely variable The target cell type of the inflammatory damage is not defined Inflammatory lesions of the prostate are more common than CaP The “inflammatory” hypothesis for CaP has not been widely accepted among scientists No systematic classification of atrophic and inflammatory lesions of the prostate was done before 2006 Common features of atrophic lesions • The epithelium is composed of two layers consisting of basal cells and luminal cells • Luminal cells are nearly flat with extremely scant cytoplasm and sometimes dark appearance at low magnification. • The two layers may be difficult to discriminate by standard H&E staining. • The basal layer can be demonstrated by staining against basal cell specific cytokeratins (5/6, 34b12) or p63. • The terms PIA and PAH overlap with the latter retaining a more biological meaning. • PAH is the only atrophic lesion correlated to the development of CaP Atrophy/PAH/PIN NORMALITY NORMAL NORMAL HYPERPLASIA ABNORMALITY PRECANCER DYSPLASIA CANCER IN SITU CANCER ? INFLAMMATION ATROPHY PAH PIN INVASIVE CANCER Platinum Slide Series Relationship between age, metabolic syndrome, inflammation, hormonal alterations, and benign prostatic hyperplasia (BPH). CANCER Briganti A, et al. Eur Urol Suppl 2009;13:865-871 From well-adapted to starvation and fighting infection to poorly adapted to overnutrition and excess inflammation Platinum Slide Series 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 Post-Atrophic Hyperplasia • Acini of PAH are smalland arranged in a lobular distribution around a dilated ‘‘feeder’’ duct, similarly to breast lobules • The number of acini per unit area is increased compared to the normal epithelium but It’s debated if there is actual “hyperplasia” • Possible moderate nucleolar enlargement can lead to diagnostic confusion with CaP • Most of the lesions contain at least some chronic (rarely acute) inflammatory cells • This is the only lesion that has been related to CaP