Cancer Biology

2 Outline 1.How do cancer cells differ from normal cells? Tumor progression 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, Men 289,550 Women 270,100 26%Lung & bronchus 15%Breast 10%Colon & rectum 6%Pancreas 6%Ovary 4%Leukemia 3%Non-Hodgkin lymphoma 3%Uterine corpus 2%Brain/ONS 2% Liver & intrahepatic bile duct 23% All other sites Lung & bronchus31% Prostate9% Colon & rectum 9% Pancreas6% Leukemia4% Liver & intrahepatic4% bile duct Esophagus4% Urinary bladder3% Non-Hodgkin 3% lymphoma Kidney3% All other sites 24%

Cells within a tissue are normally highly organized and tightly regulated e.g. intestinee.g. skin

Cancer cells exhibit behaviors found in normal cells during development differentiation, and homeostasis Cancer: an aberration of normal development

Cancer cells exhibit behaviors found in normal cells during development differentiation, and homeostasis However, cancer cells put together suites Of cell behaviors in problematic ways And 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 Molecular Biology of the Cell (© Garland Science 2008) Most normal cells stop proliferating under contact inhibition in vitro in vivo

Figure Molecular Biology of the Cell (© Garland Science 2008) Cancer cells do not exhibit contact inhibition

However cells of early embryos also 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 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 O 2 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)

41 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