Cancer Biology Figure 20-1 Molecular Biology of the Cell (© Garland Science 2008) metastatic tumors

Cells within a tissue are normally highly organized and tightly regulated Cells of a certain type are restricted to proper area Cell proliferation is tightly controlled What happens if this regulation is disrupted?

Cancer Cells Losing Control

US Mortality, 2004 Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, Heart Diseases652, Cancer553, Cerebrovascular diseases150, Chronic lower respiratory diseases121, Accidents (Unintentional injuries)112, Diabetes mellitus 73, Alzheimer disease 65, Influenza & pneumonia 59, Nephritis 42, Septicemia 33, RankCause of Death No. of deaths % of all deaths

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%

This Lecture properties of cancer cells tumor progression what causes cancer? oncogenes and tumor-suppressor genes accumulation of mutations

Cancer: an Aberration of Normal Development Cancer cells exhibit behaviors found in normal cells during development & differentiation. However, these behaviors are separated from developmental 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

Cancer cells are "immortalized”, just like stem cells, but w/o control. tumor Properties of Cancer Cells

Figure Molecular Biology of the Cell (© Garland Science 2008) Normal cells stop proliferating under contact inhibition. in vitro in vivo

Figure Molecular Biology of the Cell (© Garland Science 2008) Cancer cells are not under contact inhibition. Properties of Cancer Cells

Normal cells form differentiated tissues.

Cancer cells do not form differentiated tissues. tumor Properties of Cancer Cells

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 avoid apoptosis. blue cells = breast cancer cells yellow cells = apoptotic cells Dave McCarthy and Annie Cavanagh

Cancer cells are invasive. Properties of Cancer Cells

Normal cells can be invasive at the right time and place. Seward Hung A neutrophil penetrates through blood vessels and the extra-cellular matrix as part of an inflammatory response

Cancer cells do not form differentiated tissues. Cancer cells are not under contact inhibition. Cancer cells are "immortalized”. Cancer cells are invasive. Properties of Cancer Cells Cancer cells avoid apoptosis.

Naming Cancers (based on the original transformed tissue) epithelial cells: carcinoma 80-90% connective tissues: sarcoma 1% blood and lymphatic systems: lymphoma, myeloma, leukemia, etc. neuroectodermal system: neuroblastoma, retinoblastoma, etc.

Naming Cancers PrefixMeaning adeno-gland chondro-cartilage erythro-red blood cell hemangio-blood vessels hepato-liver lipo-fat lympho-lymphocyte melano-pigment cell myelo-bone marrow myo-muscle osteo-bone

Tumor Progression tumor = abnormal growth of cells benign- self contained malignant- invasive

Cancer develops through gradual changes in cell morphology and properties. benign

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

Metastasis

Cancer Cells Induce Angiogenesis consequences 1. Nutrients and oxygen are supplied to the tumor. 2. New blood vessels provide as easy way out.

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

Cellular Changes Required for Metastasis Figure Molecular Biology of the Cell (© Garland Science 2008)

Molecular Changes Required for Metastasis Cells need to lose cell-cell adhesion contacts. Cells need to penetrate through the matrix.

Molecular Changes Required for Metastasis Loss of cadherins is detected in all tumors. Metastatic cells produce high concentrations of MMPs (matrix-metalloproteinases).

What Causes Cancer? random mutations (mistakes at the assembly line) inherited mutations (pre-disposition) environmental factors (chemical;physical) viral infections What Causes Cancer? Cancer : Accumulation of Mutations

The first Association Between Occupation and Cancer Percivall Pott found that chimney sweeps show substantially higher rates of skin cancer.

British chimney sweeps didn’t do anything about it. Danish chimney sweeps : a daily bath after work. Result: significant.ly lower rates of skin cancer amongst Danish chimney sweeps, compared with British, even a century later.

Figure 2.21b The Biology of Cancer (© Garland Science 2007) Yamagiwa Yamagiwa Took One Step Further Coal tar condensates induced skin carcinoma in rabbits. Chemicals can directly induce cancer. Cancer can be studied in the lab.

Figure 20-20b Molecular Biology of the Cell (© Garland Science 2008) Carcinogens = Agents that Contribute to the Formation of a Tumor

Carcinogens are not always mutagens. 100 fold increased risk for head and neck cancers = +

One Mutation is Not Enough !! A Process of Natural Selection

Cancer Cells Accumulate Chromosomal Abnormalities Figure Molecular Biology of the Cell (© Garland Science 2008)

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.

Signal transduction moves information from the cell surface to the nucleus & other cellular targets.

What Types of Genes are Mutated in Cancers? Two Broad Categories Oncogenes mutational activation of proteins Tumor suppressor genes mutational inactivation of proteins

oncogeneproto-oncogene They are similar, but NOT identical. A proto-oncogene: a normal cellular gene that can become an oncogene, upon DNA damage. Oncogenes cellular signaling machinery stuck in the ON State

An Oncogene Acts in a Dominant Fashion If oncogenes are dominant, what is the normal functions of the proto-oncogenes?

Acta Cytologica, 05 The c-myc Proto-oncogene is a Transcription Factor cell proliferation Normally, c-myc is stimulated by growth factors. c-myc cell proliferation Gene amplification turns myc into an oncogene.

What Types of Genes are Mutated in Cancers? Two Broad Categories Oncogenes mutational activation of proteins Tumor suppressor genes mutational inactivation of proteins

Oncogenes The good guys become bad guys. Tumor suppressor genes We are losing the good guys.

Figure Molecular Biology of the Cell (© Garland Science 2008) dominant recessive

Example P53: the Master Guardian Figure 9.8 The Biology of Cancer (© Garland Science 2007) Mutations in p53 can be found in >50% of tumors.

Without 2 copies of P53: no cell cycle arrest (over-proliferation) angiogenesis no apoptosis no DNA repair (more mutations)

Cancer = Accumulation of Mutations More mutations, more genetic instability, metastatic disease The K-ras proto- oncogene is mutated P53 is lost in both copies Loss of the tumor suppressor gene APC Time Benign tumor cells grow only locally and cannot spread by invasion or metastasis Malignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sites Loss of the tumor suppressor gene DCC

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%

We are Making Progress !

Before We Summarize How to read a Paper 1) What is the question addressed here? 2) How did the researchers address this question? 3) what are the results? 4) what are the conclusions? for the paper, as well as for each figure

Cancer cells do not form differentiated tissues. Cancer cells are not under contact inhibition. Cancer cells are "immortalized”. Cancer cells are invasive. Properties of Cancer Cells Cancer cells avoid apoptosis. Summary

Cancer develops through gradual changes in cell morphology and properties. Benign

What Causes Cancer? Cancer : Accumulation of Mutations random mutations (mistakes at the assembly line) inherited mutations (pre-disposition) environmental factors (chemical;physical) viral infections

The Molecular Basis Behind Cancer Oncogenes mutational activation of proteins Tumor suppressor genes mutational inactivation of proteins