Chapter 12: Cancer Biology – Flashcards
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Cancer
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Is derived from Greek word for "crab" - karkinoma Is another name for malignant tumor Not all tumors are cancer 2nd leading cause of death ~ 580,00 deaths per year
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Tumor
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Is an abnormal growth resulting from uncontrolled proliferation It serves no physiologic function Is also referred to as a neoplasm: new growth
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Characteristic of a benign tumor
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Slow growth Well- defined capsule Not invasive Well differentiated Low mitotic index Does not metastasize
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Characteristics of a malignant tumor
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Rapid growth Not encapsulated Invasive Poorly differentiated: Anaplasia High mitotic index Can spread distantly (metastasis)
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Classification/nomenclature of benign tumors
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Names according to the tissues from which they arise and include the suffix, -oma Technically not considered as 'cancer'
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Lipoma
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Benign tumor of the fat
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Leiomyoma
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Benign tumor of the smooth muscle of uterus
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Glioma
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Benign neural tumor
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Chondroma
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Benign tumor of the mature hyaline cartilage
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Classification/nomenclature of malignant tumors
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Are named according to the tissues from which they arise
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Carcinomas
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Malignant epithelial tumors - Adenocarcinoma: ducts or glands
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Sarcomas
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Malignant connective tissue tumors - Chondrosarcoma, Osteosarcoma
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Lympohmas
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Cancers of lymphatic tissue
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Leukemias
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Cancers of blood-forming cells
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Carcinoma in situ (CIS)
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Preinvasive epithelial malignant tumors of glandular or squamous origin Have not broken though the basement membrane or invaded the surrounding stroma Are not malignant
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Three prognoses for Carcinoma in situ
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Can remain stable for a long time Can progress to invasive and metastatic cancer Can regress or disappear
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Transformation (neoplasia)
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Process which a normal cell becomes a cancer cell Autonomy Lacks contact inhibition Is anchorage independent Is immortal (uncontrolled cell division) Anaplasia occurs Pleomorphic
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Autonomy
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Independence from normal cell controls
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Anaplasia
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Absence of differentiation
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Pleomorphic
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Variable size and shapes
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Characteristics of neoplastic cells
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Persistent proliferation/uncontrolled cell division - unresponsive to normal feedback mechanisms Invasive growth - penetrate adjacent tissues (digest/invade tissues) Formation of metastases - 2nd tumors, appear at sites distant from 1st degree tumor Immortality - endless divisions - telomerase, preserves telomeres Etiology - activation of oncogenes (cancer causing genes) - suppression of tumor suppressor genes - malignant transformation - chemical carcinogens, viruses & radiation (x-ray, UV, radioisotopes) - over and under production of normal genes
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Cancer causing mutations
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Cancer is predominately a disease of aging Clonal proliferation or expansion occurs - is due to a mutation - ie a cell acquires characteristics that allow it to have selective advantages over its neighbors - increased growth rate or decreased apoptosis Multiple mutations are required before cancer can develop - 4-7 specific "hits" (mutations) have to occur for full blown cancer - "step-wise" accumulation of alterations occur in specific genes
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Mutations can...
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Activate growth-promotion pathways Block antigrowth signals Prevent apoptosis Turn on telomerase Turn on new blood vessel growth (agiogeneisis) Allow tissue invasion and distant metastasis (cells migrate)
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Three genetic mechanisms that have a key role in human carcinogenesis
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Activation of proto-ocogenes Mutation of genes called tumor suppressor genes Mutation of genes involved in apoptosis
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Activation of proto-ocogenes
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Hyperactivity of growth-related gene products (oncogenes)
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Mutation of genes called tumor suppressor genes
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Loss or inactivity of gene products that would normally inhibit growth
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Mutation of genes involved in apoptosis
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Overexpression of products that prevent normal cell death or apoptosis Allow continued growth of tumors
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Point mutations
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Changes occur in one or a few nucleotide base pairs. Converts a regulated proto-oncogene to an unregulated oncogene, accelerating growth. Eg: point mutation in ras gene
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Chromosome translocation
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Piece on one chromosome is transferred to another. Eg: Myc protein (Burkitt lymphoma); Philadelphis chromosme in CML (BCR-ABL fusion protein)
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Gene amplification
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A small piece of chromosome is duplicated over and over. Results in an increased expression of an oncogene. Eg: N-Myc (neuroblastoma) ; Erb2 (breast cancer)
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CML
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chronic myeloid leukemia
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Oncogenes (accelerators)
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Are mutant genes that, in their nonmutant state (proto-oncogenes), direct protein synthesis and cellular growth. Eg: EGF, EGFR, Ras etc. (proto-oncogene)
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Tumor-suppressor genes (brakes)
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Encode proteins that, in their normal state, negatively regulate proliferation. Are also referred to as anti-oncogenes Eg: Rb, BRCA1, P53, APC etc.
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Inactivation of tumor-suppressor gene
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Allows unregulated cellular growth. Takes two hits to inactivate the two alleles of a tumor-suppressor gene. Loss of heterozygosity - Both chromosomal copies of a gene are inactivated. Gene silencing without mutation - Whole regions of chromosomes are shut off while the same regions in other cells remain active. - Does not require mutations or changes in the deoxyribonucleic acid (DNA) sequence.
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Caretaker genes
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Are responsible for the maintenance of genomic integrity. Encode proteins that are involved in repairing damaged DNA - due to errors in DNA replication - mutations caused by UV or ionizing radiation - mutations caused by chemicals and drugs Loss of function of caretaker genes leads to increased mutation rates.
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Chromosome instability (CIN)
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Appears to be increased in malignant cells. May be caused by malfunctions in the cellular machinery (regulates chromosomal segregation at mitosis). Results in - a high rate of chromosomal loss - a loss of heterozygosity and chromosomal amplification - can accelerate the loss of tumor-suppressor genes and the overexpression of oncogenes.
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Genetics and Cancer-Prone Families
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Genetic events are the primary basis of carcinogenesis. Frequency of genetic changes can be increased by exposure to mutagens & defects in DNA repair - If the mutation occurs in somatic cells, then it is not passed to future generations. - If the mutation occurs in germline cells, then it can be passed to future generations. Cancer-prone families demonstrate that inheritance of a mutated gene can cause cancer. - Epigenetics silencing ( DNA methylation, histone modification) In rare families, cancer can be inherited in an autosomal dominant fashion as a result of mutations in tumor-suppressor genes TP53, RB1, and BRCA1
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Specific pathways must be misregulated for cancer to develop.
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Cancer cells must have mutations that enable them to proliferate in the absence of external growth signals: Autocrine stimulation. Mutations subvert the antigrowth signal. For eg: -Inactivation of the tumor-suppressor retinoblastoma (Rb) - Activation of the protein kinases that drive the cell cycle (cdk)
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Alterations in Progrowth & Antigrowth Signals
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Secretion of growth factors (autocrine stimulation) Increase of growth factor receptors Mutation of the signal from cell-surface receptor in the "on" position Mutation in the Ras intracellular signaling protein Inactivation of retinoblastoma protein (Rb) tumor suppressor Activation of protein kinases that drive the cell cycle (cdk's) Mutation in the P53 gene (tumor-suppressor gene) - Suppression of normal apoptosis (blocks G1-S Phase)
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Angiogenesis
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Is the growth of new vessels. Is also called neovascularization. Advanced cancers can secrete angiogenic factors to facilitate feeding of the tumor. - Vascular endothelial growth factor (VEGF) - Platelet-derived growth factor (PDGF) - Basic fibroblast growth factor (bFGF)
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Telomeres and Immortality
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Body cells are not immortal and can divide only a limited number of times (Hayflick limit). Telomeres: Are protective caps on each chromosome that are held in place by a telomerase. Telomeres become smaller and smaller with each cell division. Cancer cells can activate telomerases, leading to continued division.
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Inflammation, Immunity, ; Cancer
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An efficient immune system suppresses many developing malignancies. Defects in the immune system - increase the risk of viral-associated cancers - but have a minimal effect on the risk of others Immunotherapy can be either active or passive. - Active: Immunization with tumor antigens to elicit or enhance the immune response against a particular cancer - Passive: Injecting the patient diagnosed with cancer with antibodies or lymphocytes directed against the tumor-associated antigens
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Immune System ;Viral-Associated Cancers
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Several viruses have been associated with human cancer. Epstein-Barr virus (EBV): -.Burkitt lymphoma ( in areas of endemic malaria) ; nasopharyngeal carcinoma. Kaposi sarcoma herpes virus (KSHV) : AIDS Human T-cell lymphotropic virus type 1 (HTLV-1) - adult T-cell leukemia and lymphoma (ATLL). Human papillomavirus (HPV- 16, 18, 31 ; 33 and others) - Is implicated in cervical cancer. (Gardasil/cervarix vaacines) Chronic hepatitis B infections: liver cancer (20X chance) Chronic hepatitis C infections: liver cancer
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Inflammation as a Cause for Cancer
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Chronic inflammation: Is an important factor in the development of cancer. Active inflammation predisposes a person to cancer. - By stimulating a wound-healing response that includes proliferation and new blood vessel growth Susceptible organs - Gastrointestinal (GI) tract, pancreas - Thyroid gland - Prostate, urinary bladder - Pleura, skin
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Inflammation as a Cause for Cancer Examples
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Ulcerative colitis for 10 years or more have up to a 30-fold increase in developing colon cancer. Risk of lung cancer among women with chronic asthma is increased. Increased enzyme cyclooxygenase-2 (COX-2) generates prostaglandins in acute inflammation. - Is associated with colon and some other cancers. - Long-term, high-dose use of nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin, inhibits COX-2, thereby reducing the risk of colon cancer.
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Bacterial Cause of Cancer
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Helicobacter pylori - Chronic infections are associated with: - Peptic ulcer disease - Stomach carcinoma - Mucosa-associated lymphoid tissue lymphomas - This bacteria can both directly and indirectly produce genetic and epigenetic changes in infected stomachs. - Mutations in the p53 gene (TP53) - Alterations in the methylation of specific genes
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Successful tumors manipulate cells of the inflammatory and immune responses by...
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Induction of cellular proliferation Induction of neovascularization Induction of local immune suppression All of the above benefit cancer progression and increase resistance to chemotherapeutic agents
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A tumor-associated macrophage (TAM) is the key cell that promotes tumor survival by...
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Block cytotoxic T cell and natural killer (NK) cell functions. Produces cytokines that are advantageous for tumor growth and spread (TGF beta ; MMP) Secretes angiogenesis factors (VEGF).
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Metastasis
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spread of cancer cells from the site of the original tumor to distant tissues and organs through the body.
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Metastasis is a complex process that requires cells to have many new abilities.
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Invade Survive Proliferate in a new environment Recruit new blood vessel growth
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Beginning of Cancer Growth- Tumor
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1. Normal : cell growth is controlled cell number remains the same (Growth factor receptors are regulated) 2. Normal control is disrupted, cell number increases (GF-R degregulated and /or overexpressed) 3. Gradual increase in number of dividing cells - growing mass of tissue called a "tumor" 4. Cancer cells invade surrounding tissue and blood vessels 5. Cancer cells are transported by the circulatory system to distant sites 6. Cancer cells reinvade and grow at new location
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Invasion: Local spread
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prerequisite for metastasis and the first step Cancer spreads first to regional lymph nodes ; then to distant organs through the bloodstream. Invasion requires cancer attach to specific receptors and survive in the specific environment (integrins, CXCR4-R)
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Detachment and Invasion
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Cancer cells secrete protease (MMP) Proteases digest the extracellular matrix and basement membranes. - Create pathways through which cells can move. Metastatic cells travel in the blood and lymphatic circulation. Metastatic cells survive in a new environment.
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Epithelial-mesenchymal transition (EMT)
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Many epithelial-like characteristics (e.g., polarity, adhesion to basement membrane) are lost. Migratory capacity increases. Resistance to apoptosis increases. Dedifferentiation to a stem cell-like state favors growth in foreign microenvironments and the establishment of metastatic disease.
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Diagnosing and staging
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Involves the size of the tumor, the degree to which it has invaded, and the extent of the spread. Stage 1 - Is confined to its organ of origin. Stage 2 - Is locally invasive. Stage 3 - Has advanced to regional structures. Stage 4 - Has spread to distant sites.
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Paraneoplastic syndromes
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Symptom complexes are triggered by a cancer Not caused by direct local effects of the tumor mass. Are caused by biologic substances released from the tumor (e.g., hormones- serotonin) or by an immune response triggered by the tumor. Can be life threatening
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Pain with cancer
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Is associated with the late stage of cancer. Cause: - Pressure, obstruction, invasion of sensitive structures, stretching, tissue destruction, and inflammation
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Fatigue with cancer
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Is the most frequently reported symptom of cancer and cancer treatment. Suggested causes - Sleep disturbance, biochemical changes secondary to the disease and its treatment, psychosocial factors, level of activity, nutritional status, and environmental factors
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Cachexia
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Most severe form of malnutrition ; leads to progressive wasting Manifestations: Anorexia, early satiety, weight loss, anemia, asthenia, taste alterations, and altered protein, lipid, and carbohydrate metabolism
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Anemia
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Mechanisms (iron malabsorption in cancers) - Chronic bleeding ; results in iron deficiency, severe malnutrition, chemotherapy, radiation, or malignancy in blood-forming organs
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Leukopenia and thrombocytopenia
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Chemotherapy drugs and radiation are toxic to bone marrow.
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Tumor Markers ; its importance
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Are substances produced by benign or malignant cells. Are found on or in a tumor cell, in the blood, in the spinal fluid, or in urine. - Hormones - Enzymes - Genes - Antigens - Antibodies Tumor markers are used to: - Screen and identify individuals at high risk for cancer. - Diagnose specific types of tumors. - Observe the clinical course of cancer.
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Liver and germ cell tumors
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Secrete a protein known as alpha fetoprotein (AFP) into the blood.
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Prostate tumors
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Secrete prostate-specific antigen (PSA) into the blood.
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If a tumor marker, itself, has biologic activity:
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Symptoms are expressed. A phenomenon known as a paraneoplastic syndrome occurs.
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Choice of cancer therapy is based on
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Diagnosis Prognosis Therapeutic options by the individual, family, and medical team
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Types of cancer therapy
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Chemotherapy/Targeted chemotherapy - hormones and biological modifiers Radiation therapy Surgery Brachytherapy Alternative therapies
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Major Toxicities of Cancer Chemotherapy
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Bone marrow suppression: - Neutropenia ,thrombocytopenia, anemia GI tract injury - Stomatitis (inflammation of oral mucosa), diarrhea Nausea and Vomiting (Emotogenic potential- trigger CTZ ) Alopecia ( hair loss) Hyperuricemia : allopurinol to suppress uric acid Extravasation can occur with IV leakage = injury Reproductive toxicity: - fetal death/malformation , irreversible sterility in males Unique toxicities - doxirubicin (heart), vincristine (peripheral nerves) Carcinogenesis - Cancer can result from drug induced damage to DNA
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Obstacles to Chemotherapy
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1. Toxicity to normal cells: lack selectivity 2. Cure requires 100% cell kill (level of detection ~ 1 billion cells) - 1st order kinetics of cell kill: any given dose constant number killed go from 109 to 107 or 103 to 10 (same dose every round) Symptoms may improve, tolerate more therapy? - Host defenses in chemotherapy: drugs immunosuppressive 3. Absence of true detection: need more tests - Pap test, mammogram, endoscopy ?colonscopy, HPV vaccines 4. Solid tumors: Larger, less responsive than smaller - Debulking: reduce by surgery or irradiation - recruit cells out of G0 into cell cycle (more susceptible to chemotherapy) 5. Drug resistance decreased uptake, Increased efflux, decreased drug activation, increased repair of drug-induced DNA damage 6. Heterogeneity of tumor cells: subpopulation of dissimilar cells 7. Limited drug access (e.g. CNS, large solid tumors)
