Cancer lecture

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!