PATHOPHYSIOLOGY Name Chapter 9, Part 1: Biology of Cancer and Tumor Spread I. Cancer Characteristics and Terminology Neoplasm new growth, involves the overgrowth of tissue to form a neoplastic mass (tumor). May be benign or malignant. A. Benign vs. Malignant Tumors Benign growth is relatively slow and orderly, and tumor remains localized. Malignant characterized by rapid, disorderly growth and aggressive invasion into adjacent normal tissue. o May metastasize to another part of the body (benign tumors, by definition, never do this). Benign Malignant Grow slowly Grow rapidly Well-defined capsule Not encapsulated Not invasive Invasive Well differentiated Poorly differentiated Low mitotic index High mitotic index Do not metastasize Can spread distantly (metastasis) B. Cell Differentiation Transformation process of a normal cell becoming a cancer cell. Cancer cells exhibit autonomy and anaplasia. o Autonomy cancer cell is independent from normal cellular controls. o Anaplasia loss of cellular differentiation; cancer cell reverts to a less mature form. Differentiation normal process by which a cell develops specialized functions, organization and other more mature characteristics. Cancer cells often de-differentiate. Pleomorphic anaplastic cells have a variable size and shape (normal cells are more uniform). C. Classification and Nomenclature 1. Benign tumors - named according to the tissues from which they arise, and include the suffix -oma. For example lipoma, glioma, chondroma 2. Malignant tumors - named according to the cell type from which they originate. o Carcinomas - malignant epithelial tumors Adenocarcinomas - malignant glandular tumors o Sarcomas - malignant connective tissue tumors o Lymphomas - cancers of lymphatic tissue o Leukemias - cancers of blood-forming cells o Carcinoma in situ (CIS) preinvasive epithelial malignant tumors of glandular or squamous cell origin that have not yet broken through the basement membrane of the epithelium or invaded the surrounding stroma.
2 ACTIVITY 1: Match the terms with their descriptions. a. Anaplasia b. Autonomy c. Neoplasia d. Benign 1. Abnormal, proliferating cells possessing a higher degree of autonomy than normal cells. 2. Lack of cellular differentiation or specialization; primitive cells. 3. Slow growing mass of cells that remains at the original site. 4. Cancer cells independence from normal cellular controls. D. Classification by Histology and Genetics Histological examination of biopsied tissue is used to diagnose and classify tumors. Immunohistochemical analysis of genetic alterations is used to analyze protein expression Genetic testing is done to identify specific mutations. Example breast cancer is typed according to: o Hormone receptor status (estrogen and/or progesterone positive or negative) o Growth factor receptor status (HER2 positive or negative) Allows for improved treatment since different types respond to different treatments. E. Tumor Markers Tumor cell markers (biologic markers) are substances produced by cancer cells or that are found on plasma cell membranes or in the blood, CSF, or urine. Examples hormones, enzymes, genes, antigens or antibodies. o Hormones may be over-secreted by tumors of glandular tissue (as in pheochromocytoma, a cancer of the adrenal medulla which over-secretes adrenaline). o Alpha-fetoprotein (AFP) is secreted by liver and germ cell tumors. o Prostate-specific antigen (PSA) is secreted by prostatic carcinomas. Tumor markers are used to: 1. Screen and identify individuals at high risk for cancer 2. Diagnose specific types of tumors 3. Observe clinical course of cancer II. Genetic Basis of Cancer A. Cancer involves the transformation of normal cells into cells that exhibit: Decreased need for growth factors to multiply Lack of contact inhibition Anchorage independence Immortality
3 B. Cancer-Causing Mutations Cancer is predominantly a disease of aging. As we age our cells accumulate mutations, some of which may lead to cancer. Clonal proliferation or expansion - as a result of a mutation, a cell may acquire characteristics that allow it to have selective advantage over its non-mutant neighbor cells, such as increased growth rate or decreased apoptosis. This gives rise to an early stage tumor. Multiple mutations are required before cancer can develop. C. Oncogenes and Tumor-Suppressor Genes Proto-oncogenes normal genes that direct protein synthesis and cellular growth. Oncogenes form when the genes above are mutated so that they are no longer under normal control; cause increased cell division. Tumor-suppressor genes - encode proteins that in their normal state negatively regulate proliferation. Also referred to as anti-oncogenes. D. Mutations that Create Oncogenes Point mutations changes in one or a few nucleotide base pairs that release a gene from regulation. Most common way that oncogenes form. Example: ras gene. Chromosome translocation a piece of one chromosome is transferred to another where the oncogene is overexpressed ( myc gene in Burkitt s lymphoma) or a new protein is made that acts as an oncogene (BRC-ABL fusion in chronic myeloid leukemia). Gene amplification duplication of a small piece of chromosome over and over; results in an increased expression of an oncogene (N-myc in neuroblastomas and erbb2 in breast cancer). E. Tumor-suppressor Genes Normal functions slow cell cycle, inhibit proliferation from growth signals, and stop cell division when cells are damaged. o Examples Rb (retinoblastoma) gene normally strongly inhibits the cell division cycle; p53 induces apoptosis in damaged cells. Mutation of tumor-suppressor genes - allows unregulated cellular growth; however, both copies of the gene must be inactivated before the cell is released from inhibition. Loss of heterozygosity o The first mutation is often a point mutation in one allele. o The second mutation is often loss of an entire region of the homologous chromosome that contains the normal tumor suppressor gene. This unmasks the point mutation. o Loss of heterozygosity loss of a chromosome region in a tumor (this is where the normal, heterozygous copy was located).
4 Epigenetic gene silencing o Whole regions of chromosomes are shut off while the same regions in other cells remain active. o Occurs on one member of a pair of homologous chromosomes. o This is a normal cellular process that occurs by methylation of DNA. o In cancer cells, silenced regions sometimes spread to turn off tumor suppressor genes. o This can also unmask point mutations on the other chromosome. Chromosome instability increased in cancer cells; this results in a higher rate of chromosome loss, loss of heterozygosity and chromosome amplification in cancer cells than normal. ACTIVITY 2: Answer the following questions. 1. Why is it necessary for BOTH copies of a tumor suppressor gene to be knocked out in cancer cells? 2. What is the difference between loss of heterozygosity and gene silencing? F. Guardians of the Genome Caretaker genes code for proteins that are involved in repairing damaged DNA. o When these are damaged, the cell has an increased rate of mutation. G. Genetics and Cancer-Prone Families Genetics of cancer usually caused by genetic mutations in somatic cells during the lifetime of the individual. Thus they are genetic events, but NOT inherited. o Mutagen exposure can increase a person s risk of developing mutations. Cancer-prone families - if the mutation occurs in germline cells, it can be passed to future generations. o Predispose offspring to a specific form of cancer. o Such mutations are in tumor-suppressor genes and caretaker genes. H. Types of Gene Mutations in Cancer 1. Alteration of progrowth signals o Autocrine stimulation cancer cells gain the ability to secrete their own growth factors. o Increased growth factor receptors so they respond more to normal levels of growth factor. o Signal from cell-surface receptor is mutated in the on position so cell is signaled to divide even in the absence of growth factors. Example - mutation in the ras intracellular signaling protein
5 2. Alteration of antigrowth signals o Inactivation of Rb tumor suppressor (the normal Rb gene inhibits cell growth) o Activation of protein kinases that drive the cell cycle o Mutation in the p53 gene causes a cell to avoid apoptosis (they no longer undergo programmed cell death when there is excess growth like a normal cell would). 3. Mutations that allow metastasis o Decreased cell-to-cell adhesion o Secretion of proteases that digest surrounding barriers o Ability to grow in new locations I. Angiogenesis As tumors grow in size they need their own blood supply to deliver oxygen and nutrients to support their rapid mitosis. Angiogenesis is the process of new blood vessel formation. Advanced cancers can secrete angiogenic factors (like VEGF) that stimulate formation of vessels in the area around them. Avastin (an anticancer drug) is a monoclonal antibody that inactivates VEGF. J. Telomeres and Immortality Body cells are not immortal and can only divide a limited number of times. Telomeres are protective caps on each chromosome which become smaller and smaller with each cell division. Telomeres are maintained in germ cells and stem cells (which are immortal) by the enzyme telomerase. Cancer cells are able to produce telomerase, which allows their chromosomes to divide an unlimited number of times. III. Inflammation, Immunity and Cancer A. Inflammation and Cancer Chronic inflammation is an important factor in the development of cancer. o Examples liver cancer (HBV and HCV infections); colon cancer in people with ulcerative colitis; lung cancer in people with chronic asthma. Inflammation is associated with cancer through a number of processes: o Cytokine and growth factor release from inflammatory cells stimulates local cell proliferation. o Free radicals released by inflammatory cells cause DNA damage and mutations. o Angiogenesis is stimulated by inflammatory cells and interleukins. o Increases in the enzyme which generates prostaglandins (COX-2) are associated with colon cancer and others. NSAIDs (which inhibit COX-2) appear to protect against development of colon cancer.
6 B. Immune Protection against Viral-Associated Cancers A healthy immune system protects against viral-associated cancer. Immunosuppression fosters cancer o Non-Hodgkin lymphoma (10X) - Epstein-Barr virus (EBV) o Kaposi sarcoma (1000X) human herpesvirus 8 (HHV8) In some cases cancer promotes secretion of cytokines that foster cancer. At the same time, other immune system cells exert antitumor effects. C. Viral Causes of Cancer Implicated in about 15% of human cancers worldwide. Hepatitis B and C viruses (HBV and HCV) chronic infections cause chronic liver inflammation which contributes to about 80% of all cases of hepatocellular carcinoma. Human papillomavirus (HPV) infects basal skin cells and causes warts. Some subtypes are associated with cervical, anogenital, and penile cancer. HPV inserts into chromosomes where it can cause overexpression of oncogenes. Vaccines are now available to HPV (Gardasil and Cervarix) which prevent infection and subsequent cancer. Epstein-Barr virus (EBV) acute infection causes infectious mononucleosis. Persistent infections can result in B cell lymphomas, especially in immunosuppressed individuals. Kaposi s sarcoma herpesvirus (KSHV, also known as HHV8) associated with Kaposi s sarcoma in elderly males and immunocompromised individuals. Human T cell leukemia lymphoma virus (HTLV) a retrovirus that is linked to development of adult T cell leukemia and lymphoma. Inserts into DNA and can be inherited by offspring or passed to others through breastfeeding and other body fluids. Only a very small percentage of individuals infected with these viruses actually develop the related cancers. D. Bacterial Cause of Cancer Helicobacter pylori chronic infections are associated with: o Peptic ulcer disease o Stomach carcinoma o Mucosa-associated lymphoid tissue lymphomas in gastric wall H. pylori infections can be treated with antibiotics, which often results in regression of lymphomas. IV. Cancer Progression and Metastasis A. Metastasis the spread of cancer cells from the site of the original tumor to distant tissues and organs throughout the body. Metastasis is a defining characteristic of malignancy. B. Local Spread First step in the progression of cancer.
Several mechanisms facilitate the local spread of cancer. These include: o Cellular proliferation o Angiogenesis o Release of lytic enzymes which cause tissue degradation and digestion of barriers o Decreased cell-to-cell adhesion o Increased motility of tumor cells 7 The size of tumors increases when the rate of cellular proliferation exceeds the rate of cell death. As the tumor grows, it exerts mechanical pressure on surrounding tissues. As this pressure increases, the tumor sends projections into the surrounding tissue. The multiple projections arising from the central tumor mass give it a crab-like appearance, which gave rise to the term cancer. Pressure on nearby blood vessels can lead to local tissue ischemia, making it easier for the tumor to expand into these tissues. C. Patterns of Spread Two distinct mechanisms give rise to patterns of metastatic spread. 1. Cancer cells spread through lymphatic vessels (most common route) and blood vessels (usually veins), as well as natural tissue planes. Clusters, single cells, and fragments of tumor can disseminate by these routes. 2. Organ tropism - different cancers selectively metastasize to different sites. ACTIVITY 3: o Breast cancer often spreads through the bloodstream to bones but rarely to kidney or spleen. o Lymphomas often spread to the spleen but uncommonly spread to bone. o Selectivity is likely due to specific interactions between the cancer cells and specific receptors on the small blood vessels in different organs. Cancer cells that detach from tumors in most parts of the body often metastasize to the lungs. Cancer cells that arise in the abdomen commonly metastasize to the liver. 1. Explain, in terms of patterns of venous blood flow, why cancers from most parts of the body tend to metastasize to the lungs. 2. Explain why cancers from the abdominal organs tend to metastasize to the liver.
8 D. Stages of Cancer Spread Four stage system - categorizes solid malignant tumors for their invasion and metastasis potential. o Stage I cancer is restricted to its organ of origin. o Stage II cancer is locally invasive. o Stage III cancer has spread to regional structures such as lymph nodes. o Stage IV cancer has spread to distant sites. Cancers caught in earlier stages generally have a better prognosis.