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

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

Cancer Cells lose all controls

We are Making Progress !

US Mortality, 2004 No. of deaths % of all deaths Rank Cause of Death 1. Heart Diseases 652,486 27.2 2. Cancer 553,888 23.1 3. Cerebrovascular diseases 150,074 6.3 4. Chronic lower respiratory diseases 121,987 5.1 5. Accidents (Unintentional injuries) 112,012 4.7 6. Diabetes mellitus 73,138 3.1 7. Alzheimer disease 65,965 2.8 Influenza & pneumonia 59,664 2.5 Nephritis 42,480 1.8 10. Septicemia 33,373 1.4 Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

2007 Estimated US Cancer Deaths* Men 289,550 Women 270,100 Lung & bronchus 31% Prostate 9% Colon & rectum 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4% bile duct Esophagus 4% Urinary bladder 3% Non-Hodgkin 3% lymphoma Kidney 3% All other sites 24% 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 cancer is, by far, the most common fatal cancer in men (31%), followed by prostate (9%), and colon & rectum (9%). In women, lung (26%), breast (15%), and colon & rectum (10%) are the leading sites of cancer death. The most abundant cancer in male is prostate, the most abundant cancer in women is breast (both= ~33%) ONS=Other nervous system. Source: American Cancer Society, 2007.

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

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. Properties of Cancer Cells Most normal cells have a limited potential to divide. senescent cells

Normal Stem Cells can Divide Indefinitely, but Under Tight Control

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

Normal cells stop proliferating under contact inhibition. in vitro in vivo Figure 20-29 Molecular Biology of the Cell (© Garland Science 2008)

Properties of Cancer Cells Cancer cells are not under contact inhibition. 2 Figure 20-29 Molecular Biology of the Cell (© Garland Science 2008)

Normal cells form differentiated tissues.

Properties of Cancer Cells 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 Cancer cells are invasive. normal tissue invasive tumor Figure 20-17 Molecular Biology of the Cell (© Garland Science 2008)

Normal cells can be invasive at the right time and place. Dave McClay Seward Hung

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

Naming Cancers epithelial cells connective tissue muscle tissue epithelial cells: carcinoma 80-90% connective tissues: sarcoma 1% blood and lymphatic systems: lymphoma, leukemia, etc. neuroectodermal system: neuroblastoma, retinoblastoma, etc.

Naming Cancers Prefix Meaning 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

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

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

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

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

Metastasis

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

Cellular Changes Required for Metastasis Figure 20-44 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).

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

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. A sad British chimney sweep Result: significantly lower rates of skin cancer amongst Danish chimney sweeps, compared with British, even a century later.

A happy Danish Chimney Sweep at work with the family

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. Yamagiwa Figure 2.21b The Biology of Cancer (© Garland Science 2007)

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

+ = Carcinogens are not always mutagens. Specifically alarming: many of these carcinogens are found in cigarette smoke In many cases Carcinogens are also mutagens, but there are also other cases. Carcinogens can “help” a cancerous cell without creating a mutation. For example, the risk of getting certain mouth and throat cancers is increase a 100 fold if a person is a serious smoker and consumes distilled alcohols. Ethanol is not a mutagen, but it has toxic effects on the epithelial cells lining the mouth and the throat. The reaction of the body: stimulating proliferation. The problem: if a cell is already mutant and over proliferative, it will be the first to react to this stimulus. As a result, there will be a clonal expansion of this cell and its descendants and more possibilities for one of them to acquire more mutations Carcinogens are not always mutagens. 100 fold increased risk for head and neck cancers + =

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

Cancer Cells Accumulate Chromosomal Abnormalities Figure 20-13 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. Figure 20-7 Molecular Biology of the Cell (© Garland Science 2008)

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

Cancer at the Molecular Level 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

They are similar, but NOT identical. Oncogenes proto-oncogene oncogene They are similar, but NOT identical. A proto-oncogene: a normal cellular gene that can become an oncogene, upon DNA damage.

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

cellular signaling machinery stuck in the ON State Oncogenes cellular signaling machinery stuck in the ON State one mutated copy = over active protein = over proliferation, over-survival, etc.

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

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

dominant recessive Figure 20-27 Molecular Biology of the Cell (© Garland Science 2008)

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

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

How to read a Paper Before We Summarize for the paper, as well as for each figure 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?

Summary Cancer cells exhibit behaviors found in normal cells, but in cancer these behaviors are not under control. tumor Cancer develops through gradual changes in cell properties. Various factors lead to accumulation of DNA damage- cancer. Oncogenes and tumor-suppressor genes are the molecules behind cancer.