Oncology

Cancer More than 100 forms of the disease Almost all tissues can spawn cancer and some tissues can produce several types Each type of cancer has some unique features but Basic processes appear to be quite similar

Cancer One cell with genetic mutations Uncontrolled cell reproduction Additional genetic mutations in daughter cells as abnormal cells multiple Tumor Additional mutations Metastasis

Multistage Theory of Carcinogenesis Initiation Promotion Progression

Multistage Theory of Carcinogenesis Initiation –Alteration in structure and function of DNA with little change in structure or function caused by exposure to carcinogen which may include Radiation Chemical exposures Viral infections

Multistage Theory of Carcinogenesis Promotion –Process in which initiated cell is stimulated to become malignant –May affect initiated cell by Stimulation of cell division Interfering with differentiation –Promoters may include: chemicals, drugs, hormones, nutritional factors, wound healing, developmental stage

Multistage Theory of Carcinogenesis Tumor Progression –Evolution of progressively more malignant cells and development of metastatic colonies –May be influenced by Hormone responsiveness Growth rate Invasiveness Additional mutations Drug resistance Host defense response

Multistage Theory of Carcinogenesis

Characteristics of Cancer Cells Altered Cell Structure Altered Cell Interactions Reduced Requirements for Growth Immortality Production of different proteins Altered Metabolism Increased uptake of glucose Circumvent normal controls on growth Secrete enzymes that enable them to invade neighboring tissues and move through tissue

Cancer is a Genetic Disorder Abnormal behaviors in cancer cells are the result of genetic mutations Cells become progressively more abnormal as more genes become damaged Genes that are responsible for DNA repair eventually become damaged creating more genetic havoc

Genetic Mutations Two main categories of mutation –Point mutations: changes that alter only a few nucleotides in the DNA –Chromosomal mutations: changes involve the breakage and movement of chromosome fragments.

Chromosomal Mutations: Translocations Breakage and repositioning of chromosomal segments BCL-2 codes for a membrane protein. In B cell leukemia, the gene is translocated from the normally quiet area on 14 to a very actively transcripted area on chromosome 18 and the BCL-2 protein is expressed at very high levels. Normally B lymphocytes do their job and die. In B cell leukemia, the abnormal cells persist and reproduce. Chromosome 18 14

Chromosomal Mutations: Translocations Philadelphia Chromosome –Occurs in chronic myelogenous leukemia –Results from a translocation between chromosomes 9 and 22 –The abl gene from chromosome 9 is repositioned next to the bcr gene on chromosome 22. Together these form the Philadelphia chromosome –The two genes are fused and produce a hybrid abl-bcr protein –Abnormal protein acts to increase rate of mitosis and prevent cell death

Chromosomal Mutations: Amplification Many copies of a segment of a chromosome are produced leading to multiple copies of selected genes. If over- expressed area contains an oncogene, dysregulation of cell growth can occur.

Epigenetic Changes These changes do not alter the DNA or chromosome but do influence activity of the genes –Methylation: addition of methyl group to DNA inactivate the gene –Acetylation: addition of an acetyl group causes loosening of the DNA-Histone interaction and allows more gene expression

Mutations DNA can be altered by Spontaneous mutations Unrepaired replication errors Random molecular events Induced mutation Radiation Chemical mutagens Chronic inflammation Oxygen radicals Viral Mutations Inherited Mutations BRCA 1 and BRCA 2 associated with breast and ovarian cancers MSH2 mutation leads to hereditary non-polyposis colorectal cancer Rb mutation leads to retinoblastoma, osteogenic sarcoma and others types of cancer

Viruses Associated with Cancer RNA VirusesCancer Human T cell leukemia virus (TCLV ) T cell leukemia Lymphoma Mammary tumor virusBreast carcinoma DNA Virus Human papilloma virusCervical cancer Ebstein-Barr virusAfrican Burkett’s lymphoma Nasopharyngeal carcinoma Hepatitis BHepatocellular carcinoma

Mutations Accumulate Over Time

The Genes of Cancer Two main groups –Genes whose products stimulate division and survival of cells Normal copies of these genes are called proto-oncogenes Mutated copies of these genes are call oncogenes –Genes whose products prevent cell division or lead to cell death are called suppressor genes

The Genes of Cancer Normal regulation of cell function depends on a balance between –genes that stimulate cell division and survival and –genes that prevent cell division or regulate cell death (apoptosis)

The Genes of Cancer Proto-oncogenes are like the gas pedal of the car. When functioning properly, the car moves only when the gas pedal is pushed. Oncogenes cause the gas pedal to be stuck in the “on” position Suppressor genes act like the brakes. Each copy of the suppressor gene acts like one part of the brake system. If both copies of a suppressor gene is mutated, the car has no brakes

Oncogenes produce proteins that function as:

Oncogenes: HER 2/Neu Gene that codes for epidermal growth factor receptor 2 found on cell membranes Amplified in 30% of breast tumors Over-expression of this gene in tumor cells is associated with poor cellular differentiation and decreased patient survival Trastuzumab (Herceptin) is a monoclonal antibody that binds the HER 2/NEU protein and blocks its activity, thereby preventing cellular replication

Oncogenes: RAS The RAS protein acts like relay switch that leads to activation of genes that regulate cell division and differentiation When a growth factor binds a receptor, the RAS protein sends a message to divide to the nucleus When RAS is over-expressed the positive signals for cell division outweigh the negative signals and the cell divides When RAS is mutated the relay switch is stuck in the “ON” position, continually telling the cell to divide even when it should not

Oncogenes: RAS Mutated RAS has been found in many tumor types –Pancreas90% –Colon50% –Lung30% –Thyroid50% –Ovarian15% –Breast, skin, liver, kidney and some leukemias

Other Important Oncogenes MMPs: matrix metalloproteases Mdr: multiple drug resistance –Codes for pump that removes toxins from cell. May be amplified in cancer cells, pumping out chemotherapeutic agents and decreasing their effectiveness

Suppressor Genes Act to inhibit cell division A loss of function of the gene leads to cancer Act as the brakes on cell division Generally both copies must be ineffective for cancer to develop/progress

Suppressor Gene: p 53 Found to be defective in ~50% of tumors Functions as the guardian of the genome and conductor of a network of proteins that monitor the health of a cell Acts a transcription factor for several genes, including p21 which prevent cell division This allows a cell time to repair its DNA. If repair is not successful, p53 promotes apoptosis

Suppressor Gene: Rb Normally function includes: –binds with transcription factors to prevent cell division –promotes apoptosis –post-translational processing of proteins Mutated in several types of cancer including retinoblastoma, osteosarcomas and carcinomas Mutations may be sporadic or familial

Suppressor Gene: BRCA Mutations associated with subsets of breast and ovarian cancer but also found in prostrate, pancreatic, colon and other cancers Mutations may be inherited or arise spontaneously An important BRCA function is the repair of DNA. When this function is impaired, cells are more vulnerable to new mutations in DNA

Genetic Mutations and Development of Cancer For cancer to occur at least three genetic aberrations must be present –One to push cell to unrelenting cell division –One to inactivate signals for cell to stop dividing –One to release “brake” on cells life span Other genetic derangements are usually present as well Additional mutations develop as rapid cell divisions proceeds

Tumor Progression Hyperplasia Dysplasia In situ tumor Invasive tumor Metastasis

Summary Cancer is caused by genetic mutations which –Promote cell division –Prevent cell death –Promote tumor survival and spread Identifying the specific mutations –Predicts progression and prognosis –Identifies molecular targets for better treatments

Mr. B’s Story Mr. B. is a 56 year old man who fell while cleaning the gutters. An x-ray, taken to rule out a fractured rib, revealed a small shadow in the upper lobe of his right lung. A subsequent CT scan indicated the spot was suspicious for cancer and surgery was performed to remove the mass. Analysis of the tumor revealed non-small cell lung carcinoma. Based on clinical and pathologic characteristics the tumor was staged as IA.

Mr. B’s Story Mr. B’s physicians explain that –Stage IA indicates a small, early tumor without evidence of spread –The current standard for treatment of patients with stage IA NSCLC is surgical resection without adjuvant chemotherapy. –Studies show that 25% of these patients will relapse after initial surgery and have a poor prognosis. This subgroup of patients would probably benefit from chemotherapy. –However, chemotherapy poses significant risks also. The physicians believe that, based on clinical staging of IA, the risks of chemotherapy outweigh the benefits and they recommend close follow up without chemotherapy. Mr. B. and his wife accept their advice but are very worried about recurrence of the cancer.

Question Since the current clinical staging system for NSCLC has limitations in determining prognosis and optimal treatment, is there a way to identify whether Mr. B. is among the 25% at risk for relapse who would benefit from chemotherapy?

Question Similarly, patients with stages IB, IIA, and IIB routinely receive chemotherapy after surgery even those a subgroup of these patients are unlikely to relapse. Is there a way to identify these low risk patients and eliminate their exposure to the risks of chemotherapy?