Cancer Cancer Is an umbrella term covering a range of conditions characterized by unscheduled and uncontrolled cellular proliferation. 1 Molecular Biology of Cancer

Topics to be covered in the course The hallmarks of cancer (Introduction to the biology of cancer) Cell Proliferation, Differentiation and cell death  Control of cellular proliferation (cell cycle)  Control of Apoptosis  External control of cell cycle (Signal Transduction) Molecular carcinogenesis  Cellular transformation  Oncogenes  Tumor-Suppressor Genes  Recurring Chromosome Rearrangements and Cancer-Associated Gene Mutations in Human Cancer Molecular mechanisms involved in carcinogenesis  Alterations of Signaling to Cell Division and Survival in Cancer.  Mechanisms of Regulation of Cancer-Related Genes Invasion and Metastases Tumor Angiogenesis Molecular Biology of Cancer2

References Holland-Frei Cancer Medicine 6th edition (April 2003):  By Donald W., Md Kufe, Raphael E., Md Pollock, Ralph R., Md Weichselbaum, Robert C., Jr., Md Bast, Ted S., MD Gansler By BC Decker Molecular Mechanisms of Cancer (2007)  By Georg F. Weber Introduction to the Cellular and Molecular Biology of Cancer (2005)  By Margaret A. Knowles and Peter J. Selby Molecular Biology of Cancer3

Exams and homework Midterm exam (30 degrees) Final Exam (30 degrees) Assay (10 degrees) Homework (10 degrees) 4Molecular Biology of Cancer

The hallmarks of cancer 5 Molecular Biology of Cancer

Overview With few exceptions, cancers are derived from single somatic cells and their progeny. The emerging neoplastic cells accumulate a series of genetic or epigenetic changes that lead to changes in gene activity, and thus to altered phenotypes. Ultimately, a cell population evolves that can disregard the normal controls of proliferation and territory and become a cancer. Molecular Biology of Cancer6

Six hallmark features of the cancer cell phenotype 1. disregard of signals to stop proliferating 2. disregard of signals to differentiate 3. capacity for sustained proliferation 4. evasion of apoptosis 5. Invasion 6. angiogenesis Molecular Biology of Cancer7

Tumors arise from normal tissues Tumor is not a foreign mass invading the body from outside world Molecular Biology of Cancer8 continuity between normal and cancerous tissue in the small intestine

Four major types of new tissue growth 9Molecular Biology of Cancer

In normal skin, each cell division gives rise to one cell that retains the capacity to divide and one that differentiates. Comparison of normal and neoplastic growth in the epithelium of the skin 10Molecular Biology of Cancer

The uncontrolled cells of a cancer can grow as:  A solid mass, which is called a tumor.  Unconnected and free-floating, as in a cancer of blood cells, e.g., leukemia The term neoplasm, meaning “new growth”, is used to refer to many kinds of cancer to signify an abnormal growth. 11Molecular Biology of Cancer

Tumors are of two basic types 1. Benign:  A tumor mass contained, e.g. by a capsule of connective tissue  not able to spread 2. Malignant:  Tumor cells that escape from their site of origin and move off to grow elsewhere  The distant sites of growth are called “metastases.” 12Molecular Biology of Cancer

A Malignant Tumor vs a Benign Tumor 1. Malignant tumors invade and destroy adjacent normal tissues. Benign tumors grow by expansion, are usually encapsulated, and do not invade surrounding tissue.  Benign tumors may, however, push aside normal tissue and become life-threatening if they press on nerves or blood vessels. 13Molecular Biology of Cancer

A Malignant Tumor vs a Benign Tumor 2. Malignant tumors metastasize through lymphatic channels or blood vessels to lymph nodes and other tissues in the body. Benign tumors remain localized and do not metastasize.  Primary tumor – tumor growing at the anatomical site where tumor progression began and proceeded to yield this mass  Metastatic tumor – tumor forming at one site in the body, the cells of which are derive from a tumor located elsewhere in the body 14Molecular Biology of Cancer

A Malignant Tumor vs a Benign Tumor 3. Malignant tumor cells tend to be anaplastic (less differentiated) than normal cells of origin. Benign tumors usually resemble normal tissue more closely than malignant tumors do.  Anaplasia: reversion to a less differentiated structure 4. Malignant tumors usually, but not always, grow more rapidly than benign tumors.  Once they reach a clinically detectable stage, malignant tumors generally show evidence of significant growth, with involvement of surrounding tissue, over weeks or months,  benign tumors often grow slowly over several years. 15Molecular Biology of Cancer

A Malignant Tumor vs a Benign Tumor 5. Malignant neoplasms continue to grow even in the face of starvation of the host  They press on and invade surrounding tissues, often interrupting vital functions.  The most common effects on the patient are cachexia (extreme body wasting), hemorrhage, and infection. 16Molecular Biology of Cancer

usually Comparison of benign and malignant growths _____________________________________________ FeatureBenignMalignant _____________________________________________ Metastasisnoyes Invasionnoyes Edgesencapsulatedirregular Growth ratelowhigh Nuclei & nucleolinormalvariable, irregular Life-threateninguncommonusual _____________________________________________ Molecular Biology of Cancer17

Epithelium-derive neoplasms The most common types of human cancers The neoplasms which are derived from epithelium are called “carcinomas”. These tumors are responsible for more than 80% of the cancer-related deaths. Most of the carcinomas fall into two major categories:  Squamous cell carcinomas: arising from stratified squamous epithelium  Adenocarcinomas: arising from glandular epithelium. 18Molecular Biology of Cancer

Nonepithelial cancers Sarcomas:  Derive from a variety of mesenchymal cell types: fibroblasts (connective tissues), adipocytes (fat), osteoblasts (bone), myocytes (muscle)  constituting ~1% of the tumors in the oncology clinic. 19Molecular Biology of Cancer

Nonepithelial cancers Cancers arise from various cell types of blood-forming tissues:  lymphoma – solid tumors of lymphocytes, most frequently found in lymph nodes  leukemia – tumors of “white cells” of the blood, usually moving freely through the circulation 20Molecular Biology of Cancer

Nonepithelial cancers Tumors arising from cells of the central and peripheral nervous system:  Glioblastoma tumors of astrocytes 21Molecular Biology of Cancer

“oma” usually indicates a tumor.  carcinoma, sarcoma, lymphoma, myeloma, neuroblastoma, etc. Rarely, the “oma” describes a nonneoplastic conditions.  granuloma, is a mass of granulation tissue resulting from chronic inflammation or abscess. 22Molecular Biology of Cancer

Classification of Human Tumors by Tissue Type Tissue of OriginBenignMalignant Epithelium Surface epithelium Glandular epithelium Papilloma Adenoma Carcinoma Adenocarcinoma Connective tissue Fibrous tissue Bone Fibroma Osteoma Fibrosarcoma Osteosarcoma Endothelial tissue Blood vessels Lymph vessels Hemangioma Lymphangioma Hemangiosarcoma Lymphangiosarcoma Neural tissue & its derivatives Glial tissue Meninges Nerve sheath Melanocytes Retina Glioma Meningioma Neurofibroma Pigmented nevus - Glioblastoma multiforme Meningeal sarcoma Neurofibrosarcoma Malignant melanoma Retinoblastoma 23Molecular Biology of Cancer

Cell Proliferation and Differentiation The biology of cell division, differentiation, and apoptosis is exceedingly similar in both normal and cancer cells. The cancer cell differs from its normal counterpart in that it is aberrantly regulated.  Cancer cells like normal cells generally contain the full complement of biomolecules necessary for: survival, proliferation, differentiation, cell death, and expression of many cell type-specific functions.  Failure to regulate these functions properly, however, results in an altered phenotype and cancer. Molecular Biology of Cancer24

Four cellular functions tend to be inappropriately regulated in a neoplasm 1. The normal constraints on cellular proliferation are ineffective. 2. The differentiation program can be distorted:  The tumor cells may be blocked at a particular stage of differentiation.  They may differentiate into an inappropriate or abnormal cell type. 3. Chromosomal and genetic organization may be destabilized:  variant cells arise with high frequency.  Some variants may have increased motility or enzyme production that permits invasion and metastases. 4. The tightly regulated cell death program (apoptosis) may be dysregulated. Molecular Biology of Cancer25

PROLIFERATION Molecular Biology of Cancer 26

One hallmark of cancer is that most are genetically clonal, Cancers usually arise by expansion of a single cell. Evidence from X-inactivation  Red and blue colors indicate cells with one or the other X chromosome inactivated.  Note that all the cancerous cells that form the “tumor mass” in the middle of the tissue show only one kind of X- inactivation, suggesting that they all grew as a clone from a single cell. 27Molecular Biology of Cancer

Cancer evolves through continual genetic evolution of mutant cells by a process of natural selection. In cancers in which preneoplastic lesions can be identified, the preneoplastic cells are likely to be genetically distinct from the overtly neoplastic cells.  Genetically abnormal cells are generated as a result of environmental insult or normal errors in replication.  Some small fraction of these cells escapes normal controls on cell proliferation and increases their number.  As this pool of mutant cells proliferates, additional mutant variants are continuously generated. If the result of these additional mutations provides a selective growth advantage, then the mutant variant will increase its relative number.  Through multiple rounds of proliferation, mutation, and selection a neoplastic variant evolves to cause cancer. 28Molecular Biology of Cancer

Two parameters will critically affect the rate of this clonal evolution The mutation rate, and the rate of proliferation.  The rate of neoplastic transformation will increase with mutations that increase the rates of proliferation or mutation rate.  Such mutations are more likely to be detected in cancer cells than other types of mutations.  If such a mutation is inherited, the incidence of cancer within such a family is expected to be significantly higher than normal. 29Molecular Biology of Cancer

The accumulation of multiple mutations in a single somatic cell is very improbable The probability of mutation is low (one in about 100 million/base pair/cell division) To get mutations that alter genes that control cellular behavior is VERY unlikely To get mutations in many different genes that control cell behavior is VERY VERY unlikely! The road to cancer therefore seems to involve the introduction of abnormal instability into the genome of the cell that is becoming cancerous 30Molecular Biology of Cancer

A “successful” cancer is one that acquires just the right degree of genetic instability, allowing it to mutate at rates that give it selective advantages but not so fast that it dies Molecular Biology of Cancer31