CANCER: THE BASICS

… and a little more too.

Dr. Steven R. Patierno Executive Director

“But not all these tragic consequences together are the worst evil wrought by cancer. For everybody that is killed by the fact of cancer, multiplied thousands of minds are unnerved by the fear of cancer. What cancer, as an unsolved mystery, does to the morale of millions who may never know its ravages is incalculable. There is an incidence of cancer that cannot be reached by the physician’s medicaments, the surgeons knife, or any organized advice against panic. Nothing but the conquest of cancer itself will remove this sword that today hangs over every head.” Glenn Frank, President, University of Wisconsin, 1936.

The Top Ten Google “News” searches in 2006 ACCORDING TO USA TODAY AMERICA IS CONCERNED ABOUT CANCER

CANCER: WHAT IS IT?
CANCER IS A DISESASE IN WHICH ONE CELL, OR A GROUP OF CELLS, ACQUIRE THE CAPABILITY TO PROLIFERATE INDEFINATELY AND TO INVADE DISTANT SITES AND ORGANS

CANCER: IS IT NEW?
TUMORS HAVE BEEN FOUND ON DINASAUR BONES AND MUMMIES
Paleontologists Teach Medical Students About Fossil Tumors June 1, 2006 — Using medical-physics tools such as CT scans, medical students can learn to recognize a tumor even in a 150-million-year-old dinosaur bone.

AN ANCIENT EGYPTIAN PAPYRUS (1600BC) HAD A HEIROGLYPHIC OF A TUMOR ON A PENIS AND WRITING DESCRIBING THE TREAMENT OF A BREAST GROWTH BY CAUTERIZATION BY A FIRE DRILL.

CANCER: IS IT NEW?
Hippocrates, the great Greek physician (460-370 B.C), Hippocrates noticed that blood vessels around a malignant tumor looked like the claws of crab. He named the disease karkinos (the Greek name for crab). In English this term translates to carcinos or carcinoma.
Galen 200AD to 16th century: Cancer caused by “excess black bile”.

Ramazzini 1700: breast cancer in nuns Pott 1775: scrotal cancer in chimney sweeps Bichat 1800s: cancer a tissue Muller 1800s: cancer made of cells

CANCER: WHERE DOES IT COME FROM? HOW DOES IT BEGIN?
25% (1 in 4) of all humans on the planet will get or die from cancer Up to 25% in developing countries: HPV, HepB, HepC, H.Pylori Environment: oxygen, chemicals etc

Individual Life Risk: Men 1:2, Women 1:3

Smoking

Living and Eating

CANCER: WHERE DOES IT COME FROM? HOW DOES IT BEGIN?
SOME CONTEXTUAL BACKGROUND The vast majority of genetic damage and mutations are the inevitable consequences of life, for example: Background Radiation and Oxidative Stress Natural Chemicals in Food (cooked and uncooked) Natural Chemicals in Bodily Waste Products Non-anthropogenic hydrocarbons like volcanic eruptions

CANCER: WHERE DOES IT COME FROM? HOW DOES IT BEGIN?
SOME CONTEXTUAL BACKGROUND The majority of DNA damage and “mutations” are probably endogenous and/or stochastic Estimated that the DNA in each of our cells get his with 200,000 damaging events per day Nearly a third of our total complement of genes is dedicated to DNA repair This developed long before the Industrial Revolution

CANCER: WHERE DOES IT COME FROM? HOW DOES IT BEGIN?
SOME MORE CONTEXTUAL BACKGROUND At the “population” level cancer is a frequent disease: 25% of all humans will either get cancer or die from it. At the “cellular” level cancer is a very “rare” event, occurring in only 1/4 people with 100,000,000,000,000 (100 trillion) cellular targets per person Not everybody with similar chemical exposures gets cancer People exhibit hereditary susceptibility to specific exposures

CANCER: WHERE DOES IT COME FROM? HOW DOES IT BEGIN?
SOME MORE CONTEXTUAL BACKGROUND Tumors are monoclonal (from one cell) in origin and cancer requires accumulation of genetic changes A background of cancer rates can be expected as a statistically pre-determined consequence of the stochastic risks associated with aging It is also influenced by personal and cultural behavior superimposed on hereditary susceptibility GENE-ENVIRONMENT INTERACTIONS

A CRITICAL CONCEPT: RANGE OF POTENCY

THE TARGET

THE PROCESSOR

THE RESULT: DNA MUTATIONS
AND PROTEINS WITH ALTERED OR NO FUNCTION

The Emergent Tumor: Progeny of One Stubborn Cell In Normal Self-renewing tissues there is balance: HOMEOSTASIS Proliferation << >> Death

The Emergent Tumor: Progeny of One Stubborn Cell In Cancer there is a loss of balance

THE MULTI-STEP PROCESS

CLONAL SELECTION/EXPANSION

The Emergent Tumor: Progeny of One Stubborn Cell: From a Pathologist’s Viewpoint
Hyperplasia: Increase in Cell Number Metaplasia: Replacement of Cell Type Dysplasia: Variation in Size, Shape, Organization Anaplasia: Intracellular & Growth Changes Neoplasia: New growth, Relatively Autonomous Growth

The Emergent Tumor: Progeny of One Stubborn Cell: From a Pathologist’s Viewpoint Benign Growth: Encapsulated, non-invasive, low mitoses, high differentiation, slow growth, little anaplasia, not metastatic Malignant Conversion: Non-encapsulated, locally invasive, variable differentiation, higher mitotic index, more rapid growth, typical anaplasia, metastatic

The Emergent Tumor: Progeny of One Stubborn Cell The Main Themes of Cellular Dysregulation Disruption of Cell Cycle Regulation: Failure of Arrest and Restraint Escaping the Death Default: Resilience to Apoptosis and Senescence Cell Interrupted: Loss of Communication and Integration Genomic Instability: Acceleration towards conversion

The Emergent Tumor: Progeny of One Stubborn Cell:

CONVERSION

*Predominantly epigenetic *Up- and dis-regulation of transcriptional activity *Gross Chromosome abnormalities *Further disruption of cell cycle circuitry *Activation and secretion of invasion-associated cell surface molecules

Progression Past Malignant Conversion Escaping Immune Recognition, Angiogenesis, Invasion, Metastasis

HISTORICAL PERSPECTIVE
PROTO-ONCOGENES AND ONCOGENES
Normal gene activated to become oncogenic by mutations, chromosomal rearrangement, or amplification.
In order to be a protooncogene or become an oncogene the normal gene must be a gene that controls a critical component of cell growth/death.

MOLECULAR CARCINOGENESIS

MOLECULAR CARCINOGENESIS

MOLECULAR CARCINOGENESIS

MOLECULAR CARCINOGENESIS

HISTORICAL PERSPECTIVE
TUMOR SUPPRESSOR GENES
Normal genes that normally suppress growth or promote death. Contribute to oncogenesis by being inactivated by mutations or negative epigenetic silencing (hypermethylation).

MOLECULAR CARCINOGENESIS

MOLECULAR CARCINOGENESIS
Genes Defining the Emergent Tumor
A USEFUL MODEL PROPOSED BY KINZLER AND VOGELSTEIN

GATEKEEPERS AND CARETAKERS
GATEKEEPERS: GENES WHICH RESTRAIN CELL GROWTH AND DIRECTLY SUPPRESS NEOPLASIA CARETAKERS: GENES WHICH AFFECT SUSCEPTIBILITY AND INDIRECTLY SUPPRESS NEOPLASIA

MOLECULAR CARCINOGENESIS
Genes Defining the Emergent Tumor GATEKEEPERS
INHIBIT CELL CYCLE INDUCE APOPTOSIS INDUCE SENESCENCE OR TERMINAL DIFFERENTIATION

CARETAKERS
DNA REPAIR: MAINTENANCE OF GENOMIC STABILITY METABOLIC PHENOTYPE

MOLECULAR CARCINOGENESIS
Genes Defining the Emergent Tumor GATEKEEPERS GONE BAD
DYSREGULATED CELL CYCLE: p53, p21, RB1 INHIBIT or FAIL to INDUCE APOPTOSIS: Bcl-2

CARETAKERS
BROKEN DNA REPAIR: ATM (Ataxia Telangiectasia Mutated) BRCA1, BRCA2 FA (Fanconi Anemia)

Chromosomal Distribution of some Oncogenes and Tumor Suppressor Genes.

The New Biology of Cancer

How to Make A Cancer

Cell 100; 57, 2000

What’s in the future?

Molecularly Targeted Cancer Therapeutics

The forefront of a new wave in Oncology: Developing novel noncytotoxic therapeutic strategies for controlling malignant progression by inhibiting tumor cell growth and the spread of cancer known as Metastasis.
“…a new, comprehensive molecular understanding of cancer… will transform cancer from a death sentence into a chronic but manageable disease.” U.S. News & World Report, June 24, 2002.

The Goal of Inhibiting Tumor Progression

Science, 295, March 29, 2002

THE ULTIMATE GOAL?
By controlling tumor growth and metastasis, we aim to “manage” it in the same way that diseases such as hypertension and diabetes are managed.

One of the first “bullseye” MTDs

Chronic Myelogenous Leukemia (CML)
Reciprocal translocation: Chromosome 9 & 22 (Philadelphia Chromosome) Creation of a unique fusion protein Bcr/Abl, a non-membrane bound oncoprotein (p210) This unique tyrosine kinase is capable as a sole-transforming event in mice.

In human CML, activation of the Bcr/Abl oncogene leads to disease progression through further phenotypic and genotypic instability leading to mutations in p53, loss of p16, loss of INK41/caf exon 2, and loss of the retinoblastoma (RB).

Chronic Myelogenous Leukemia (CML)
Reciprocal translocation: Chromosome 9 & 22 (Philadelphia Chromosome)

Chronic Myelogenous Leukemia (CML)
Prior to Gleevec Allogeneic hematopoietic stem cell transplantation: potentially curative but carries significant risk of mortality and is restricted to young patients with a suitable donor. Interferon alpha: high rates of cytogenetic and hematological responses but 5 year survival rate of only 57%. Side effects nothing short of awful.

After Gleevec Gleevec: at 5 years 98% still at Complete Hematologic Response, and 87% at Complete Cytogenetic Response.

Future cancer treatment using antiparticles from the exotic "antiworld"

Antiprotons do not belong to our world An antiproton is a so-called antiparticle. It is thus part of the mirror world that also consists of the positron – the electron’s antiparticle – as well as other exotic particles. A common feature of them all is that they are not normally found in our world. Unfortunately, the promising results will first benefit the treatment system in ten years at the earliest. This is partly because producing antiprotons is expensive…….

“Experiments indicate promising future for nanotechnology in cancer treatment” “Experiments on mice have shown promise for the future of nanotechnology in treating cancer.” “The research brings doctors one step closer to being able to inject patients with nanoparticles that bore inside tumors and release powerful doses of cancer-killing drugs while leaving the rest of the body unscathed.”

After seeing how the mice were cured of human prostate cancer with the technology, cancer specialists gathered at the -------- on Tuesday praised the work as impressive and said they had high hopes for its application to patients.

But, genetically and medically speaking, not everybody is the same…

Genomic Medicine………

Monitor the activities of tens of thousands of genes simultaneously to identify novel targets

……. is it Personalized Medicine?

A major problem that needs to be at the heart of our efforts: Eliminating Cancer Disparities • The District of Columbia has some of the highest cancer mortality rates in the United States. • Because of the high minority population, and extensive health care barriers, cancer disparities are particularly severe. • DC is an acute microcosm of the national challenge of the unequal burden of cancer.

An Important Lesson
Disparities range across the health care continuum
• The same barriers that interfere with access to quality cancer Treatment, also interfere with Cancer Prevention and Control, utilization of available Screening, access to and utilization of Support Services (support groups, palliative care, end of life care), and long term Survivorship.

A Novel Genomics Partnership
• Genomics of Cancer Disparities

Gene profiles derived from prostate biopsy tissue: Hierarchical Clustering Analysis comparing African American and Caucasian samples

Transcriptome Co-Expression Mapping

Prostate Cancer Differential Gene Networks in African American Men

Genomics of Breast Cancer Disparities

Gene network analysis reveals new targets: Uteroglobin (UG) expression in normal prostate

Loss of UG in PC Progression

Cancer BPH

INHIBITION OF CELL GROWTH PC-3 ARE GROWTH ARRESTED BY CHRONIC EXPOSURE TO rUG (daily, not cumulative)

Growth Curve: PC-3 and rUG
400,000 300,000 200,000 100,000 0
Da y1 Da y Da 2 y Da 3 y Da 4 y5
120 100
% Control (Cell Count)
Cell Counts

Inhibition of PC-3 Cell Growth by Uteroglobin 8-6-02

Control mean 5 mcg/ml mean 10mcg/ml mean 20 mcg/ml mean

80 60 40 20 0 10 0 EC50= 0.66µM 10 1 10 2 10 3 10 4

Day

[Uteroglobin, ηM]

Rat Aorta Angiogenesis

Untreated

rUG 30ug/ml

Effect of rUG on PC-3 tumor nodule formation in CAM assay

Control

rUG
(30 ug/ml to CAM)

1.00

Survival Distribution Function

0.75

0.50

0.25

20 mg/kg Control

0.00 0 10 20 30 Days 40 50 60

Kaplan-Meier Survival Analysis: Overall Group Differences

Model for Analysis of Population Health and Health Disparities
Culture, Norms, Racism, Sexism Discrimination, Public Policies, Poverty

Social Conditions and Policies

Health Care System, Families, Churches, Community-based organizations, Legal System, Media, Political System

Institutions

Fundamental Causes

Upstream Factors

Social/Physical Context Collective Efficacy, Social Capital, Access to Resources, Social Cohesion, Segregation, Neighborhood Disadvantage, Neighborhood Stability

Downstream Factors

Social Networks, Social Support Social Influences, Social Engagement

Social Relationships

Social and Physical Context

Disparate Health Outcomes

Age, SES, Education, Obesity, Tobacco Use, Acculturation, Diet, Race

Individual Risk Factors

Individual Demographic and Risk Factors Biologic Responses and Pathways
Warnecke et al., AJPH 2008

Allostatic Load, Metabolic Processes, Physiological Pathways, Genetic Mechanisms

Biologic/Genetic Pathways

Cancer Economics Institutional Context & Social Conditions and Policies Prevention Discrimination Barrier s Psychology of Low-income and urban neighborhoods Disease mapping Family stress Coverag e Poverty Public Policy

The New Science of Cancer: Cells to Society
Biological Pathways & Responses
Genomics Pharmacogenomics

Mouse models

Biopsy samples and analysis

Racial differences

Social and Physical Context Access to services Environmental Geography

SES Exercise Unemployment

Epidemiology of Breast Cancer Diet

Risk Factors (ex-obesity)

Man's inhumanity to man is not only perpetrated by the vitriolic actions of those who are bad. It is also perpetrated by the vitiating inaction of those who are good. --- Martin Luther King, Jr.

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