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03.30.11Cancer Biology

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Outline

1.How do cancer cells differ from normal cells?

• Tumor progression

2.Molecular basis for cancer

Cancer is the second leading cause of death in the U.S.

Epithelial cells: carcinomas 80-90%Connective tissues: sarcomas 1%Blood and lymphatic systems: leukemias, lymphomas Neuronal system: neuroblastoma, retinoblastoma, etc.

Epithelial cells

Connective tissue

Muscle tissue

Cancer may be derived from many tissues

2007 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2007.

Men289,550

Women270,100

26% Lung & bronchus

15% Breast10% Colon & rectum 6% Pancreas 6%Ovary 4% Leukemia 3%Non-Hodgkin

lymphoma 3% Uterine corpus 2%Brain/ONS 2% Liver & intrahepatic

bile duct23% All other sites

Lung & bronchus 31%Prostate 9%Colon & rectum 9%Pancreas 6%Leukemia 4%Liver & intrahepatic 4%

bile ductEsophagus 4%Urinary bladder 3% Non-Hodgkin 3%

lymphoma Kidney 3%All other sites 24%

Cells within a tissue are normally highly organized and tightly

regulated

e.g. intestine e.g. skin

Cancer cells exhibit behaviors found in normal cells during development differentiation, and homeostasis

Cancer: an aberration of normal development

Cancer: an aberration of normal development

Cancer cells exhibit behaviors found in normal cells during development differentiation, and homeostasis

However, cancer cells put together suitesOf cell behaviors in problematic waysAnd do so out of normal regulatory controls

Most normal cells have a limited potential to divide

senescent cells

Properties of Cancer Cells

Normal stem cells can divide indefinitely, but under tight

control

Self-renewing stem cell

Differentiated cells

Cancer cells are "immortalized”,just like stem cells, but w/o control

Properties of Cancer Cells

Self-renewing stem cell

Differentiated cells

Cancer cell

Most Normal cells differentiate

But stem cells do NOT

differentiate

Like normal stem cells cancer cells do not

differentiate

tumor

Figure 20-29 Molecular Biology of the Cell (© Garland Science 2008)

Most normal cells stop proliferating under contact inhibition

in vitroin vivo

Figure 20-29 Molecular Biology of the Cell (© Garland Science 2008)

Cancer cells do not exhibit contact inhibition

However cells of early embryosalso lack contact inhibition

Normal “Transformed”

Cancer cells exhibit altered cell adhesion and cytoskeletal organization

These changes in cell shape and behavior are shared by many migrating cells,including those that migrate into wound sites

Late stage cancer cells are invasive

Figure 20-17 Molecular Biology of the Cell (© Garland Science 2008)

normal tissue

invasive tumor

Normal cells can be invasive at the right time and place

Normal cells that are starved for O2

Induce Angiogenesis

Consequences 1. Nutrients and oxygen are supplied to the tissue

Can’t breath!Send Blood vessels

Cancer Cells also Induce Angiogenesis

Consequences 1. Nutrients and oxygen are supplied to the tumor

2. New blood vessels provide as easy way out

Normal cells may undergo apoptosis

As part of a developmental program

when cells become “dangerous” (e.g. DNA damage)

Properties of Cancer Cells

Cancer cells escape apoptosis

Blue cells = breast cancer cells

Yellow cells = apoptotic cells

Dave McCarthy and Annie Cavanagh

Properties of Cancer Cells

• Immortalized

• Do not differentiate

• Fail to exhibit contact inhibition

• Invasive

• Escape apoptosis

Figure 20-9 Molecular Biology of the Cell (© Garland Science 2008)

Cancer develops through gradual changes in cell morphology and

properties

Tumor Progression

Tumor = abnormal growth of solid tissue

Benign- self contained

Malignant- invasive

Metastasis is a difficult and dangerous process both for the

tumor cell and the host!

Cellular changes required for metastasis

All cancers have a genetic basis and are diseases caused by mutations in

normal signaling pathways

• Random mutations (mistakes during DNA replication)

• Inherited mutations (pre-disposition)

• Viral infections

• Environmental factors (chemical; physical)

Inherited mutations may predispose individuals towards cancer e.g., Familial adenomatous polyposis (FAP)

Cancer results from a series of mutations, each cumulatively altering the cell

Hypothetical progression of colon cancer

•Mutations in 4 key genes

•Progressive changes in cancerous tumor cells

Figure 20-20b Molecular Biology of the Cell (© Garland Science 2008)

Carcinogens are chemical agents that contribute to tumor formation

Tumors evolve by repeated rounds of mutation and proliferation

Figure 20-7 Molecular Biology of the Cell (© Garland Science 2008)

The fact that cancer is a multi-step process is reflected in correlation between age and incidence of cancers

Especially late in the process, Cancer cells also accumulate chromosomal abnormalities

Karyotype from breast cancer cell•Total of 48 chromosomes (instead of 46)•Multiple chromosomal translocations

Two classes of genes are mutated in cancer:

1. Oncogenes

2. Tumor suppressor genes

Proto-oncogene: a normal cellular gene that can become an oncogene, upon DNA damage

Oncogenes

Oncogenes result from rare dominant mutations that lock signaling machinery in

the ON state

Examples of oncogenic mutations

Mutations that cause ligand-independent receptor activation(dimerization)

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Oncogenes result from rare dominant mutations that lock signaling machinery in

the ON state

Examples of oncogenic mutations

Mutations that lock Ras into the GTP-bound form

Tumor suppressor inactivation result from rare recessive mutations that lock

signaling machinery in the OFF state

Examples of oncogenic mutations

Mutations that inactivate the Retinoblastoma protein (Rb)

Tumor suppressor inactivation result from rare recessive mutations that lock

signaling machinery in the OFF state

Examples of oncogenic mutations

Mutations that inactivate p53

Also promotes cell death