• Cancer – What is it?1. What is the difference between a benign tumor and a malignant

tumor?

2. What is the difference between a sarcoma and a carcinoma?

3. Cancer forms most commonly in what tissues?

4. What are some common mechanisms thought to “cause’ cancer?

5. Are some types of cancer more “curable” than others?

True/False?• Most cancers are derived

from a single abnormal cell

• Most cancers develop due to a single mutation in a cell’s DNA

Name at least three key properties that make cells capable of cancerous growth.

• Tumors are generally traced to a single cell that has undergone a heritable change that gives it the ability to outgrow its neighbors.

• Detectable at about a billion cells or more

• Due to a genetic change (mutation) or an epigenetic change?

Genes from maternal or paternal side, can influence the production or inhibition of other genes.

Normal incidence of mutation:

10-6 mutations per gene per cell division

Lifetime accumulation of mutations:

1010 mutations in each gene

So Why Isn’t Cancer More Common?

Tumors may progressively accumulate mutations

They may grow sporadically, increasing in size when a particular advantageous mutation gives a cell a selective advantage over its neighbors

Tumors may also regress if advantageous mutations do not occur and the existing cells cannot survive in the environment they create

What characteristics give cancer cells an advantage?

• Genetic instability• Defective control of cell death or

cell differentiation• Loss of proliferation controls• Ability to survive in an alien

environment

Proto-oncogenes

Tumor suppressor genes

How would you find the identity of an oncogene?

• Find a convenient “test” cell line that already has some cancer-like characteristics

• Extract DNA from tumor cells; fragment it; transfect test cells

Examples of Cancer-Critical Genes:

Ras (oncogene)

Myc (oncogene)

Find at least two abnormalities in this human karyotype.

Pairs of chromosomes should be the same colors

What characteristics give cancer cells an advantage?

• Genetic instability• Defective control of cell death or

cell differentiation• Loss of proliferation controls• Ability to survive in an alien

environment

Myeloid leukemia

What characteristics give cancer cells an advantage?

• Genetic instability• Defective control of cell death or

cell differentiation• Loss of proliferation controls• Ability to survive in an alien

environment

Replicative cell senescence

What characteristics give cancer cells an advantage?

• Genetic instability• Defective control of cell death or

cell differentiation• Loss of proliferation controls• Ability to survive in an alien

environment

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Preferential metastatic sites

Primary tumour Common distant site (s)Breast’ adenocarcinoma Bone, brain, adrenal

Prostate adenocarcinoma Bone

Lung small cell carcinoma Bone, brain, liver

Skin cutaneous melanoma Brain, liver, Bowel

Thyroid adenocarcinoma Bone

Kidney clear cell carcinoma Bone, liver, thyroid

Testis carcinoma Liver

Bladder carcinoma Brain

Neuroblastoma Liver, adrenal

Colon adenocarcinoma in lung tissue. Glandular structure and cells very similar to colon. Necrosis internally.

Reason for organ selectivity

Mechanistic theory: determined by the pattern of blood flow.

“Seed and soil” theory: the provision of a fertile environment in which compatible tumor cells could grow

Determining factors

• Appropriate growth factors or extracellular matrix environment

• Compatible adhesion sites on the endothelial lumenal surface

• Selective chemotaxis at which the organ producing some soluble attraction factors to the tumor cells

5 major steps in metastasis

1. Invasion and infiltration of surrounding normal host tissue with penetration of small lymphatic or vascular channels;

2. Release of neoplastic cells, either or single cells or small clumps, into the circulation;

3. Survival in the circulation;

4. Arrest in the capillary beds of distant organs;

5. Penetration of the lymphatic or blood vessel walls followed by growth of the disseminated tumor cells

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Tumor invasion

1. Translocation of cells across extracellular matrix barriers

2. Lysis of matrix proteins by specific proteinasesa) MMP2 and MMP9, which cleave type IV collagen the major constituent of

basement membrane, are believed to be of special importance

b) Serine protease involved in ECM degradation are plasmin, plasminogen activators and cathepsin G.

3. Cell migration

Interaction between tumour cells and the surrounding connective tissue

1. Integrin: cell-matrix adhesion• Integrin can affect the

transcription of MMP genes

2. E-cadherin/catenin adhesion complex: cell-cell adhesion • Reduce expression of E-

cadherin and catenin increase the invasiveness of tumor cells

p120 catenin

Cell migration

1. Small Rho GTPase family

2. Motility promoting factors

Small Rho GTPase

Stimuli

Cdc42GTP

Rac1GTP

Pak1

LIM kinase

Cofilin

Actin polymerisation

MLC Kinase

MLC Phosphorylation

Contraction

Stress fibers

Detachment

Filopodia Lamellipodia

Rho GTPase is required for the transition of invasive phenotype

How Can We Mimic and Study Metastasis?

Cancers are formed viaTumor Initiators ,Tumor Promoters, or Viruses Tumor initiators – damage DNA

•Aflatoxin•Vinyl chloride•Benzene•Arsenic•Asbestos

Tumor promoters – not mutagenic themselves; promote growth and differentiation without affecting DNA. They do this via inflammatory response – causes secretion of growth factors and proteases in the local environment. Can regress if the promoter is removed (example: warts).

• palytoxin•thapsigargin

Viruses and Cancer

Major Treatments for Tumors (benign and metastatic)

Surgery

Chemotherapy

Radiation

New Treatments

Drugs http://www.chemocare.com/bio/

Retinoic Acid – •derivative of vitamin A; •used to control cell growth and differentiation; •binds to a class of nuclear receptors; •used in cancers such as skin cancers, cutaneous T-cell lymphoma, acute promyelocytic leukemia, lung cancer, breast cancer, ovarian cancer, bladder

cancer, kidney cancer, and head and neck cancers. 

Adriamycin/Doxorubicin•Cancers treated with adriamycin include: bladder, breast, head and neck, leukemia (some types), liver, lung, lymphomas, mesothelioma, multiple myeloma, neuroblastoma, ovary, pancreas, prostate, sarcomas, stomach, testis (germ cell), thyroid, uterus•Targets fast dividing cells of all types; antibiotic nature of these drugs destroys cells

Radiation (external or internal)

Brachytherapy