2. PLAN
• Epidemiology
• Cancer Biology,
• Etiology
• Cancer screening, diagnosis
• Cancer staging
• Tumor marker
• Surgical approaches to cancer therapy
• Chemotherapy, hormonotherapy, immunotherapy, Gene therapy , radiation
therapy
3. Introduction
• Incidence: New Cases/100,000
Persons per yr
• Mortality: Deaths/100,000 Persons per
yr
• Two types of epidemiologic studies
conducted to investigate cancer:
etiology and interventional modalities
• Cohort studies
• Case control studies
4. Epidemiology
• Global Statistics on Cancer Incidence
• Breast Cancer
• high in all of the most highly developed regions
except Japan
• low (<30 per 100,000 women) in most of Africa
(except South Africa) and Asia
• The lowest incidence is in Central Africa(16.5 per
100,000)
5. Epidemiology
• Global Statistics on Cancer Incidence
• Breast Cancer
• linked to cancer susceptibility genes
• mutations in these genes account for only 5 to
10% of breast tumors
• reproductive factors, diet, alcohol, obesity,
physical activity, environnemental factor
6. Epidemiology
• Global Statistics on Cancer
Incidence
• Colon and rectal cancer
• higher in developed countries
• incidence is relatively low in North
Africa, South America, and eastern,
southeastern, and western Asia
• dietary differences in consumption
of animal fat, meat, and fiber
7. Epidemiology
• Global Statistics on Cancer
Incidence
• Stomach cancer
• The incidences varies among
different regions
• Higher in Japan
• Lower in in North America,
• Lower in northern and western Africa
8. Epidemiology
• Global Statistics on Cancer
Incidence
• Stomach cancer
• The risk is increased by
• high consumption of preserved salted
foods
• infection with Helicobacter pylori
• The risk is decreased by
• high intake of fruits and vegetables
9. Epidemiology
• Global Statistics on Cancer Incidence
• Liver cancer
• 85% of liver cancers occur in developing countries
• high in China (37.9 per 100,000 men)
• low in North and South America and Europe (2.6 to 6.2 per 100,000 men)
• the major risk factors are
• infection with hepatitis B and C viruses
• consumption of foods contaminated with aflatoxin
11. Cancer Biology
• Cell Proliferation and Transformation
• Cells-unresponsive to normal growth controls
• In vitro abnormal characteristics of malignant cells:
Loss of contact inhibition An altered appearance and poor adherence
to other cells
Loss of anchorage dependence for growth
Immortalization
Gain of tumorigenicity
15. Cancer
Biology
• Oncogenes
o Oncogenes are mutated genes
involved in the regulation of cell
growth and proliferation.
.
Most mutations in
oncogenes are acquired, not
inherited.
Growth factor, growth factor
receptors, intracellular signal
transduction molecules ,
nuclear transcription factors,
etc
16. Cancer Biology
• HER2
• HER2, also known as neu or c-erbB-2, is a member of the EGFR.
• The HER2 gene is frequently amplified and the protein overexpressed in many cancers,
including breast, ovarian, lung, gastric, and oral cancers
• HER2 overexpression is associated with increased cell proliferation and anchorage-
independent growth as well as resistance to pro apoptotic stimuli and increases cell migration
and upregulates the activities of MMPs.
• Importance: Therapeutic!!!
17. Cancer
Biology
Alterations in Apoptosis in Cancer
Cells
• Apoptosis is a genetically
regulated program to dispose of
cells.
• The effectors of apoptosis are a
family of proteases called
caspases.
• Two principal molecular
pathways signaling apoptosis
The mitochondrial
pathway
The death receptor
pathway
18. Cancer Biology
Autophagy in Cancer Cells
Major cellular pathway for protein
and organelle turnover.
Autophagy is involved in the elimination of
cancer cells by triggering a nonapoptotic cell
death program
19. Cancer
Biology
Angiogenesis
• The establishment of new blood vessels
from a pre-existing vascular bed
• Essential for tumor growth and
metastasis
• Tumors develop an angiogenic
phenotype as a result of accumulated
genetic alterations and in response to
local selection pressures such as
hypoxia.
• Mediated by factors produced by various
cells, including tumor cells, endothelial
cells, stromal cells, and inflammatory
cells.
• Important molecules: VEGF, PDGF
20. Cancer
Biology
Cancer Invasion
• in situ cancer to invasive
cancer
• The ability to invade involves
Proteolysis of the extracellular
matrix (ECM).
Changes in adhesion,
Initiation of motility,
24. Cancer
Etiology
Genes Associated With Hereditary Cancer Risk
The following factors may suggest the presence of a
hereditary cancer:
Tumor development at a much younger age than usual
Presence of bilateral disease
Presence of multiple primary malignancies
Presentation of a cancer in the less affected sex (e.g., male breast
cancer)
Clustering of the same cancer type in relatives
Occurrence of cancer in association with other conditions such as
mental retardation or pathognomonic skin lesions
25.
26. Cancer Etiology
• Cancer Genetics
• BRCA1, BRCA2, and Hereditary Breast-Ovarian Cancer Syndrome
• APC Gene and Familial Adenomatous Polyposis
• Mismatch Repair Genes and Hereditary Nonpolyposis Colorectal Cancer
• RET Proto-Oncogene and Multiple Endocrine Neoplasia Type 2
• RB1 Gene and Hereditary Retinoblastoma
• P53 and Li-Fraumeni Syndrome
• hCHK2, Li-Fraumeni Syndrome, and Hereditary Breast Cancer
29. Physical Carcinogens
• Occur through;
Induction of inflammation and cell proliferation over a period of time
Exposure to physical agents that induce DNA damage
• Chronic irritation and inflammation such as chronic non-healing wounds, burns, inflammatory
bowel syndrome associated with malignancy.
• Radiation is the best-known agent of physical carcinogenesis
• Effects:
Direct: induce a spectrum of DNA lesions
Indirectly: induces genomic instability / bystander effect.
The incidence of cancer varies by geography ; genetics and environmental exposures
Cohort studies follow a group of people who initially do not have a disease over time and measure the rate of development of a disease.
A case-control study compares a group of patients affected with a disease to a group of individuals without the disease and looks back retrospectively to compare how frequently the exposure to a risk factor is present in each group to determine the relationship between the risk factor and the disease
19.3 per 100,000 women in Eastern Africa
3
5
a steady decline is being observed in the incidence and mortality rates
Male to female is 2:4
In summary, the incidence rates of many common cancers vary widely by geography\ due in part to genetic differences/ differences in environmental and dietary exposures,
essential alterations in cell physiology for malignancy to occur; target for therapy
Hanahan/Weinberg
.
Cell growth and proliferation are under strict control; cancer cells evade the control hence…
Cell type–specific carcinogenesis differences
loss of contact inhibition : Do not stop after monolayer formation
an altered appearance and poor adherence to other cells:
loss of anchorage dependence for growth: cells must be anchored to ECM to proliferate
Immortalization: indefinite cellular proliferation
gain of tumorigenicity
Phases of carcinogenesis
Gain of function of genes known as oncogenes
Loss of function of genes known as tumor-suppressor genes
The initiating events occur as
Deletions of tumor-suppressor genes
Amplification of oncogenes
Alterations at the transcription level
Mutations or alterations in the expression of cell-cycle proteins, growth factors, growth factor receptors, intracellular signal transduction proteins, and nuclear transcription factors all can lead to disturbance of the basic regulatory mechanisms that control the cell cycle, allowing unregulated cell growth and proliferation.
3 letters; Prefix “v-” for virus or “c-” for cell or chromosome,
Proto-oncogenes can be activated (show increased activity) or overexpressed (expressed at increased protein levels) There is increased activity which can be due to chromosomal translocation, gene amplification and mutation within the coding sequence as well as others
Epidermal growth factor receptor (EGFR)
The critical role of HER2 in cancer biology has been leveraged for therapeutics
monoclonal antibodies trastuzumab and pertuzumab
small molecule inhibitor lapatinib
antibody-drug conjugate ado-trastuzumab emtansine
Cancer cells must not only be able to proliferate indefinite but should also evade apoptosis.
Autop
Autophagy initiates with the progressive segregation of cytoplasmic material by double‐membraned structures commonly known as phagophores or isolation membranes. Phagophores nucleate from the endoplasmic reticulum (ER), but several other membranous organelles have been shown to contribute to their elongation, including the Golgi apparatus, ER‐Golgi intermediate compartment (ERGIC), plasma membrane, mitochondria and recycling endosomes. Completely sealed phagophores, which are known as autophagosomes, fuse with lysosomes to form autolysosomes. This promotes the activation of lysosomal hydrolases and hence causes the breakdown of the autophagosomal cargo. The products of these catabolic reactions reach the cytosol via transporters of the lysosomal membrane and are recycled by anabolic or bioenergetic circuitries.
mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy
VEGF: 6 with 3 receptors.
Induction: Hypoxia ( Plus EGF, PDGF, TNF-α, TGFβ, and interleukin-1β)
Actions : inducing endothelial cell proliferation and tube formation, Vascular permeability & dilatation, and inducing endothelial cell synthesis of proteolytic enzymes; act as an endothelial survival factor .
N.B: Controls lymphogenesis too and hence play apart in lymphatic met…
A feature of malignant cells is their ability to invade the surrounding normal tissue.
Metastasis
- Metastases arise from the spread of cancer cells from the primary site and formation of new tumors in distant sites
- Only a small subset of cancer cells is then able to initiate micro-metastases
Dormancy; Reactivatio by a physiological perturbation/ proliferative rate balanced by the apoptotic rate / loss of immunologic control of subclinical metastatic foci of disease.
The ability of cancer cells to grow in a specific site likely depends on features inherent to the cancer cell, features inherent to the organ, and the interplay between the cancer cell and its microenvironment.
The metastatic potential of a tumor is already predetermined by the genetic alterations that the cancer cells acquire early in tumorigenesis.
A genetic disease that arises from an accumulation of mutations
Somatic >70% Vs germline 20% vs both 10%
Somatic mutations in a cancer cell genome have accumulated over the lifetime of the patient.
Patients with tumors with similar histologies may differ in genetic mutation status and other molecular features
An important challenge to utilizing genomic alterations to personalize cancer therapy
During cancer progression, subclones frequently arise, resulting in differences in the proportion and pattern of genomic alterations
Hereditary cancers, the individual carries a particular germline mutation in every cell; most of which are tumor suppressor gene mutation.
Significant implications for patient and family counseling, planning of surgical therapy, and cancer screening and prevention.
Carcinogen: Any agent that can contribute to tumor formation
Currently, approximately 60% to 90% of cancers are thought to be due to environmental factors; can be Chem/ physical/ viral
Chemical grouped into 3:
1. Genetoxin- initiator/
2. Potentiate the carcinogenesis of 1 but do not in themselves cause cancers /
3. Tumor promoters, enhances tumor formation when given after exposure to genotoxins
The International Agency for Research on Cancer (IARC)
Damage to the nucleotide bases and cross-linking, and DNA single- and double-strand breaks
