Robert A Weinberg The Biology of Cancer Second

Cancer Genetics Cancer are malignant tumors 1. the deregulated cell cycle disease 2. a genetic disease due to accumulated mutations • caused by inherited mutations in a single gene • phenotypes can be predicted • the defective inherited gene is not sufficient for the development of cancer: accumulation of additional somatic mutations • heterogeneous population and aggressive 3. the evolved cells: acquire the ability to endless proliferate and to change their properties in response to many different stress 4. tumors arise from normal cells (tissues) and these disorganized tissues become a malfunctioning cells 5. Single cell origin 6. Invasive and metastatic 7. Somatic mutation; major cancer; 95 %

Normal Versus Neplastic tissue

Malignant tumors: cancerthe ability to invade surrounding tissues • • Tumors are classified into two (benign and malignant) depending on degree of aggressive growth. Tumors-benign tumors ex) cysts no spread, not invasive Malignant tumors; cancer- the ability to invade surrounding tissue Metastasis-break loose, enter the bloodstream or, lymphnodes and form a secondary cancer

Metastasis of cancer cells to distant tissue Lung of a mouse with the formation of Metastasis (melanoma cells) Metastasis in the liver with advanced colon carcinoma

Tumors derived from specialized cell types Type of cancer • Carcinoma; epithelial origin; more than 80 % of human cancer Epithelia are sheets of cells that lines the walls of cavity or channel -skin, mouth, gastrointestinal tract (esophagous, stomach, small and large intestine, mammary glands, lung, liver, ovary, gallbladder, urinary bladder etc) • Sarcoma; mesenchymal origin: connective tissue or muscle cell origin • Hematopoietic cells origin; leukemia, lymphoma • Nerve cell origins; glioma

Carcinoma • Epithelia are sheets of cells that lines the walls of cavity or channel : -skin, mouth, gastrointestinal tract (esophagous, stomach, small and large intestine, mammary glands, lung, liver, ovary, gallbladder, urinary bladder etc) Endometrium of the uterus The collecting tubule of the Kidney

Carcinoma • Two major class: – Squamous cell carcinoma arise from protective epithelial ex) skin, esophagous – Adenocarcinomas arise from secretary epithelial: secret subs into the duct or cavities that they line : ex) lung, and stomach secrete mucous layers – Other types

Epithelial derived carcinoma The squamous epithelial of the cervix The squamous epithelial of the skin The malignant squamous epithelial cells are invading the stromal/mesechymal tissue

Epithelial derived carcinoma Adenocarcinomas in stomach Mucous secreting cells in stomach Mucous secreting goblet cells in small intestine Columnar cells Adenocarcinomas in colon

Mesenchymal tumors

Mesenchymal tumors Liposarcoma: Adipocytes Leiomyosarcoma: smooth muscle Menigioma Protective covering of brain

Hematopoietic tumors

Hematopoietic tumors Acute lymphocyte Leukemia (ALLs) Acute Myelogenous Leukemia (AML) Erythroleukemia

Neuroectodermal tumors

Neuroectodermal tumors Astrocytes Molecular layer Glanular layer Glioblatsomas medulablastoma

Some other types of tumors Melanoma derived from melanocytes (neurocrest-derived cells) Small-cell lung carcinoma (SCLSs) have many neurosecretory cells ( neurocrest origin in the Adrenal Glands) -originate in endodermal cell population of the lung -epithelial and neuroectodermal properties -Trans-differentiation: switching tissue lineages

Cancer progressively develop • • The degree of abnormalities reflect the tumor progression in which a normal tissue progressively evolves into abnormal tissues. (multiple stage of tumors) Normal-hyperplastic-dysplastic-neoplastic-metastatic, but only suggestive model. • Definition of the stage of tumors • Anaplastic: dedifferentiated tumors, so histo-pathologically not to identify the origin of tumors. Typically, most of tumors have differentiated traits of their precursor

Hyperplastic : cells may abnormal with an excessive numbers of cells, but they normally form tissue Hyperplastic epithelium

Metaplasia: Tumors show a displacement with normal cell types by other normal cells that do not place at that place. Epithelial transition zone (esophagous and stomach, or cervix and uterus) Secreted cells from the lining of the stomach

Dysplastic: most of cells within a dsyplasia region are cytologically abnormal: transition stage between benign and pre-malignant • • • Variable nuclear size and shape, Increased nuclear staining, Increased level of nuclear versus cytoplasmic volume, Increased mitotic index Lack of differentiation etc

More abnormal growth can be seen Adenoma, Polyps, papillomas, warts Pre-invasive Adenoma and Carcinoma Neoplasias (mixture of benign and malignant cells) Intraductral carcinoma

DCIS: Ductal carcinoma in situ

Invasive Carcinoma ductal carcinoma of the breast Lobular Carcinoma Normal-hyperplastic-dysplastic-neoplastic-metastatic,

Tumors are monoclonal growth Single cell origin

Many cancer cells derived from a single abnormal cell -a monoclonal origin ex) CML (clonic myelgenous leukemia); caused by translocation C 9 -22; t(9; 22) - same X chromosome inactivation

Changes in glucose metabolism in cancer cells

Difference in genetic backgrounds and environments affect differentially the incidence of various tumors. Why ? Mutations are linked to cancer development ? • Different genetic factors: genetic alleles may affect the rate of cancer development: Some do, but others not • Different environmental factors may also affect the rate of cancer development: Some do, but others not • Somatic mutation; major cancer; 95 % • The great majority of cancer development are caused by external factors including life style and exposure to carcinogens

Specific chemical agents can induce cancer, especially derived from epithelial cells • 1761, Pott found that skin cancer is increased in men who worked as chimney sweep • 1915, Yamagiwa reported that coal tar directly induced cancer on the ears of rabbit • 1940, several carcinogen were purified from coal tar. • 1910. viruses cause leukemia and sarcoma • 1927, X-ray induced mutations in Drosophila • 1940, World War I mustard gas warfare, many alkylating agent are mutagenic • 1945, World War II at Hiroshima, IR significantly induced the many types of cancer

Ames test for measuring mutagenicity Many carcinogens act as mutagens. Almost all mutagenic compounds are carcinogenic, but some there are nonmutagenic carcinogens (called as tumor promoters).

Cancer cells have serious mutations and natural selection power

Mutations are linked to cancer development 1. Inherited disease (genetic factor); Rb, Brca 1 etc heritable predisposition to cancer -single gene mutations, chromosomal abnormalities. -additional somatic mutations requirements 2. Non-inherited(nongenetic) -accumulations of somatic mutations -carcinogens, abnormal hormonal control level, smoking ets

Mutations in cancers; * Subtle mutation; deletion, insertion, point mutation * Chromosomal level; Aneuploidy -somatic loss or gain of chromosome -mitotic dysjunction; normal karyotype , but loss of gene—LOH Two paternal or maternal Ch * Chromosomal translocation; balanced and unbalanced Translocation Ex) APL (acute promyletic leukemia); t(15; 17)- PML-Retinoic acid receptor. *Amplification; increased copy number of genes *Exogenous DNA; tumor virus-Viral Oncogene Cervical Cancer; Burkitts lymphoma. T cell leukemia

A single mutation is not enough to cause cancers; Do cancers occur only in patient who inherit a defective cancer genes ? No -0. 1 -10 % inherited cancer, > 90 % somatic mutation; - but they have mutations in same genes ex) Rb, colon cancer (APC) * inherited person; early onsets; -second mutation or LOH at early time— * gradual clonal expansion * LOH; selective advantage for cell survival or growth -Multiple mutations are required for developing cancers -successive rounds of mutation and *natural selection; become evolved cells -long lag phase before cancer The chance goes up steeply with ages

Loss of heterozygosity

Cancer Cells are genetically unstable; neucleotide or chromosomal levels- Aneuploidy Enhanced mutation rate; 1. defective in DNA repair or replication errors—accumulate mutations 2. chromosomal instability; mitotic abnormalities—Aneuploid

Genetic instability confer selective advantages; natural selection

Cancers are some defective in cell cycle regulation, cell death or cell proliferation Cell cycle checkpoint defects; G 1/S, S, G 2/M. Mitotic checkpoint controls,

Genes related with cancer; What genes are mutated in cancers ? Tumor suppressor, --suppress cell divisions; cell cycle controller Ex) G 1/S, G 2/M checkpoint controller Mutation(loss of function); uncontolled cell divisions & other mutations events Oncogene : promote the cell divisions Gain of functions; hyperactive Ex) Ras, EGFR active

Caretakers Gatekeepers ( ATM, Brca 1, ( p 53, Rb, ARF ets) PMS, MSH etc) Telomerase activation Oncogene activation ( Ras, Src ets) Mitogenic Signals Proliferations DNA damage Signals Cell cycle arrest & Apoptosis

Oncogenes related with cancer; -RSV (Rous Sarcoma Virus; first known oncovirus DNA virus; SV-40, polymoma, Papillomavirus, HBV Epstein-B Virus RNA virus; related with animal cancers Genes; gag, poly, env Oncogenes; v-src, able, ras. Erb associated with growth, differentiation ex; EGFR Conversion of proto-oncogenes to oncogenes

Oncogenes

To focus on the genes that cause cancers or To attempt to answer the questions; 1. What are the genes involved in cancer development 2. What is the nature of the mutations in cancers ? 3. How do these genes work ? 4. What are the implications of knowledge about genes for diagnosis and future treatment

Cancers Identification of genes Function of genes Defining of the pathways Integration of the pathways Identification of Molecular Therapeutic Targets

The protein Networks

Summary • • • Tumors are derived from normal tissues(cells), defined as a disease of malfunction Tumors can be either benign (localized, noninvasive) or malignant (invasive, metastatic) Classified into 4 major groups based on their origin: epithelial, mesenchymal, hematopoietic and neuroectodermal) Most of common tumors are of epithelial origin-the carcinoma Sequamous cell carcinoma arise from protective epithelial Adenocarcinomas arise from secretary epithelial Nonepithelial tumors – Sarcoma originated from mesenchymal cells – Hematopoietic cancers from circulatory and the immune cells – Neuroecodermal tumors from the nervous cells Anaplastic: dedifferentiated cells and not known of their origin Hyperplastic tumor: likely normal except for an excessive numbers of cells Metaplastic tissues show displacement with normal cell types by other normal cells that do not place at that place. Displastic tumors are cytologically abnormal, transition state between benign and malignant. Intact boundary created by the basemen membrane Ex); adenomna, polyps, papilloma, warts

Summary • • Metastatic tumors break the basement membrane and invade underlying tissue and are able to move and adapt to new environemtn Typical malignant tumors Most of human tumors are monoclonal (derived from single cells) rather than polyclonal Difference in genetic backgrounds and environments affect differentially the incidence of various tumors Mutation induced by either external agents (chemical agents or physical agents or virus) or internal agents (Radicals etc) causes the cancer development. Many carcinogens act as mutagens. Almost all mutagenic compounds are carcinogenic, but some there are nonmutagenic carcinogens( called as tumor promoters).