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Cancer- today find the cause: tomorrow find the cure Professor E.E.U. Akang
Medical Laboratory Science Council Of Nigeria World-wide Biomedical Laboratory Science Day Celebration 29 April, 2009
What is cancer?• A type of neoplasm (“new growth”) that
invades normal tissues and spreads (metastasises) to distant sites, i.e. malignant
• Clonal (arises from single abnormal cell)• Autonomous (not subject to growth control)• Purposeless (dysfunctional)• Detrimental to host tissue
What is the global and national burden of cancer?
• 5 million female and 6 million male new cancer cases worldwide (of which 100,000 occur in Nigeria) annually
• >6 million deaths worldwide annually• >50% of patients with cancer live in
developing countries, which have <10% of the resources for cancer therapy
Global statistics on cancer, 2002
What do we know about the history of cancer?
• Cancer is literally as old as man• 1 Sam 5:6, GNB, “The LORD punished
the people of Ashdod…by causing them to have tumours”
• Neolithic man 10,000 BC• Ancient Egypt and Peru 3,000 BC• Hippocrates 400 BC “carcinoma”
What do we know about carcinogenesis?
Carcinogenesis is a multi-hit, multi-stage process•>80% NATURE- environmentRadiation, Chemicals, Viruses- DNA/RNA, Helicobacter pylori•<10% NURTURE- genesCytogenetic, Genetic, Multifactorial, Imprinting
What do we know about the molecular genetics of cancer?• Oncogenes• Tumour suppressor genes• DNA repair genes• Metastasis genes• Apoptosis genes
Summary of factors involved in carcinogenesis
Breast cancer as a paradigm- justification
• #1 female cancer worldwide• >1 million new cases/yr• >400,000 deaths/yr• In Nigeria, breast cancer afflicts
>12,000 women/yr(GLOBOCAN, 2002)
Breast cancer is heterogeneous
Breast cancer is not a single disease, but a
spectrum of several clinical and
morphological entities, each having
distinctive natural history and prognostic
outcomes
Research themes in breast cancer
• Determination of cell of origin• Elucidation of molecular mechanisms• Identification of susceptibility genes• Classification of breast cancer
Recent advances in breast cancer
• Specific risk of malignant transformation associated with premalignant breast lesions
• Molecular mechanisms responsible for invasion and metastasis
• Characteristic signatures associated with specific subsets of breast cancer on the basis of genetic profiling
Conventional tests
• Histological typing (good vs. bad histological variants)• Histological grading (Scarff-Bloom-
Richardson)• Immunohistochemical profiling (HER2,
ER and PR status)
Molecular tests
• Fluorescence in situ hybridisation• Polymerase chain reaction• Southern blotting• Gene microarraysThese tests are applicable to surgical
biopsies, Tru-cut biopsies, FNAs, and frozen section
Gene microarray (molecular portrait)
Molecular targets in breast cancer (Cristofanilli and Hortobagyi, 2002)
Breast cancer molecular pathwaysNon-hormonal targets
Signal transductionCell growth pathways
Cell cycle apoptosisCell proliferation
AngiogenesisMicroenvironment interaction
Hormonal targetsNuclear receptor family
Cell differentiation
Non-hormonal targetsCATEGORY CLASS BIOMARKERS THERAPEUTIC
AGENTS
Signal transduction modulators
Growth factors and receptors
EGFR/HER2 Herceptin (trastuzumab)
PDGFR STI571 (imatinib mesylate)
Cell cycle regulation
Cell cycle control and apoptosis
P53 wt-p53
Angiogenesis modulation
Endothelial cell proliferation
VEGF rhuMab-VEGF
Proteases/protease inhibitors
uPA/PAI uPA inhibitors
COX2 COX2 COX2-inhibitors (e.g. celexobid)
Natural and synthetic ligands of nuclear receptor family members
RECEPTOR CATEGORY
NATURAL LIGAND SYNTHETIC LIGANDS
1. STEROIDOestrogen receptor Oestradiol TamoxifenProgesterone receptor
Progesterone Medroxyprogesterone acetate, RU486
Androgen receptor Dihydroxytestosterone Hydroxyflutamide, bicalutamide
2. NON-STEROIDVitamin D receptor 1,25-dihydroxy vitamin D EB1089, CB966Retinoid nuclear receptor (RAR)
Retinoic acid All-trans-retinoic acid
Peroxisome proliferator-activated receptor
15-deoxy-Δ-12,14-prostaglandin J2
TGZ, LY29311
Farnesoid X-activated receptor
Bile acid SR-45023A (apomine)
Molecular subtypes of breast cancer
LUMINAL Bp38 MAPK
Sonic HedgehogNotch
G1/S checkpoint Sterol
biosynthesisTGF-β, FGF
ERBB2G1/S checkpointToll-like receptor
T-cell receptorNF-κB
B-cell receptorDeath receptor
BASAL-LIKEWnt/B-catenin
G1/S checkpointGly, ser, and thr
metabolismOestrogen receptor
PPAR
NORMALJAK/Stat
PDGF, EGFPPARIFG-1
IL-6, IL-4
LUMINAL Aval/leu/ile/glu
degradationglu metabolism
VEGFIGF-1
Luminal A• High ESR1, GATA3, HNF 3A, TFF3 , KRT8
expression (luminal cell phenotype)• ER positive• Relatively good prognosis (best molecular
type)• Predicts response to methotrexate- and
paclitaxel based chemotherapy and resistance to anthracyclines
Luminal B
• ER positive tumours characterised by lower expression of luminal type genes• Have a relatively poor prognosis
Basal-like
• High expression of basal cell markers (KRT5, KRT17, LAMC2)
• On immunohistochemical analysis, these neoplasms are triple negative, lacking ER, PR and HER2 expression
• Worst prognosis of all breast cancer types• Young Hispanic and African-American
women
ERBB2+• Overexpress HER2 and are oestrogen
receptor (ER) negative• HER2 overexpression is an adverse
prognostic factor associated with poorly-differentiated, high-grade tumours, high proliferative rates and lymph node involvement
• Chemoresponsive to Trastuzumab and anthracycline-based chemotherapy
Normal-like
• Co-express genes of adipose tissue and other tissues of nonepithelial origin and genes associated more with basal epithelial cell expression than luminal epithelial cell expression
Molecular subtypes of breast cancerLUMINAL B
p38 MAPKSonic Hedgehog
NotchG1/S checkpoint
Sterol biosynthesisTGF-β, FGF
ERBB2G1/S checkpointToll-like receptor
T-cell receptorNF-κB
B-cell receptorDeath receptor
BASAL-LIKEWnt/B-catenin
G1/S checkpointGly, ser, and thr
metabolismOestrogen receptor
PPAR
NORMALJAK/Stat
PDGF, EGFPPARIFG-1
IL-6, IL-4
LUMINAL Aval/leu/ile/glu
degradationglu metabolism
VEGFIGF-1
Closing remarks
• A major challenge is to reconcile conventional morphological with new molecular classification
• Molecular studies emphasise the heterogeneity of breast cancer subtypes
• Future studies should reveal additional information of diagnostic, therapeutic and prognostic import
NIGERIAGod bless our noble fatherland, Great land of sunshine bright,
Where brave men chose the way of peace, To win their freedom fight.
May we preserve our purity, Our zest for life and jollity.
God bless our noble laboratory physicians And laboratory scientists everywhere.
Teach them to walk in unity To build our nation dear;
Forgetting “superiority”, “strife”, or speech, But caring always each for each.
Modified from “Things fall apart” by Chinua Achebe
THANK YOU FOR LISTENING!
Happy Biomedical Day!