Chapter 12 cancer biology

Inducing Angiogenesis

Angiogenesis Growth of new vessels. Also called neovascularization. Advanced cancers can secrete angiogenic factors to facilitate feeding of the tumor. • Vascular endothelial growth factor (VEGF) • Basic fibroblast growth factor (bFGF) #angiogenesis: Is the process of cancer cell growth.

Clonal proliferation (clonal expansion)

Cancer cell progeny can accumulate faster than nonmutant neighbors

intestinal polyps

#Which statement supports the hypothesis that intestinal polyps are benign neoplasms and the first stage in the development of colon cancer? An accumulation of mutations in specific genes is required for the development of cancer.

What is adjuvant chemotherapy?

1. ADJUVANT CHEMOTHERAPY: is given AFTER surgical incision of a cancer with the goal of eliminating micrometastases. 2.NEOADJUVANT CHEMOTHERAPY: given before surgery or radiation. Neoadjuvant chemotherapy can shrink tumors so that surgery may spare more normal tissue. For example: in bone cancer, neoadjuvant chemotherapy can convert a large mass to a smaller mass allowing the surgeon to perform a limb-sparing excision rather than an amputation.

What are tumor cell markers??

-During surveillance or diagnosis of cancer as well as following therapy, specific biochemical markers of tumors have proven to be helpful. -These tumor markers are substances produced by both benign and malignant cells that are either present in or on tumor cells or found in blood, spinal fluid, or urine. -Tumor markers include hormones, enzymes, genes, antigens, and antibodies. -If the tumor marker itself has biologic activity, then it can cause symptoms, 5. Tumor markers can be used in three ways: • to screen and identify individuals at high risk for cancer • to help diagnose the specific type of tumor in individuals with clinical manifestations relating to their tumor, as in adrenal tumors or enlarged liver or prostate • to follow the clinical course of a tumor.

Cancer and Chronic inflammation

5. Chronic viral hepatitis caused by hepatitis B virus(HBV) or hepatitis C virus(HCV) infection markedly increases the risk of liver cancer. 6. A specific example is the association between gastric inflammation induced by infection with the bacterium Helico bacter pylori (H.pylori) and the risk for gastric cancer.• H. pylori is a bacterium that infects more than half of the world's population .• Chronic infection with H. pylori is an important cause of peptic ulcer disease and is strongly associated with gastric carcinoma, a leading cause of cancer deaths worldwide .• It is also associated with a less common cancer, gastric mucosa-associated lymphoid tissue (MALT) lymphomas.

How do cancer cells gain access to the circulation?

Access to a bloody supply is obligatory to the growth and spread of cancer § Without a blood supply to deliver O2 and nutrients, growth of the tumor is limited In cancerous tumors several mechanisms increase and maintain secretion of angiogenic factors by the cancers cells as well as prevent release of angiogenic inhibitors § Hypoxia-inducible factor-1α (HIF-1α), an oxygen-sensitive transcription factor, is a major regulator of angiogenesis in normal tissue; HIF-1α is stabilized under hypoxic conditions and induces expression of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Inactivation of tumor-suppressor genes (like p53) or increased expression of oncogenes (HER2) leads to increased expression of HIF-1α-regulated angiogenic factors and increased vascularization. Increased expression of HIF-1α also is related to increased resistance to chemotherapy, increased tumor cell glycolysis, increased metastasis, and a poor prognosis. These effects may likely occur through an autocrine mechanism by which VEGF activates tumor- associated VEGF receptors.

Mutation

Alteration in DNA sequence affecting expression or function of a gene Point mutations: small-scale changes Driver mutations: "drive" progression of cancer Passenger mutations: random event

Caretaker genes

Are responsible for the maintenance of genomic integrity. Encode proteins that are involved in repairing damaged DNA, such as the damage that occurs with errors in DNA replication, mutations caused by ultraviolet or ionizing radiation, and mutations caused by chemicals and drugs. Loss of function of caretaker genes leads to increased mutation rates #What is the role of caretaker genes? Maintenance of genomic integrity

Enabling Replication Immortality

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 telomeres, leading to continued division. #How do cancer cells use the enzyme telomerase? To switch on the telomerase to enable cells to divide indefinitely

Reprogramming Energy Metabolism

Cancer cells perform glycolysis. Allows lactate and its metabolites to be used for the more efficient production of lipids and other molecular building blocks needed for rapid cell growth. Reverse Warburg effect: cancer cells generate large amounts of ATP

The Biology of Cancer Cells

Cancer is predominantly a disease of aging . Clonal proliferation or expansion occurs. Is due to a mutation; that is, a cell acquires characteristics that allow it to have selective advantage over its neighbors. • Increased growth rate or decreased apoptosis Multiple mutations are required before cancer can develop. Cancer heterogeneity: due to proliferation and mutation Cancer development is similar to wound healing. #Apoptosis is a(an): Normal mechanism for cells to self-destruct when growth is excessive

Chemotherapy

Eradicates enough tumor cells to enable the body's natural defenses to eradicate the remaining cells. Can be a single-agent or combination chemotherapy. Induction chemotherapy: Causes shrinkage or the disappearance of tumors . Adjuvant chemotherapy: Is administered after the surgical excision with a goal of eliminating micrometastases. Neoadjuvant chemotherapy: Is administered before localized (surgical or radiation) treatment

Malignant tumors

Rapid growth Non encapsulated Invasive Poorly differentiated: Anaplasia High mitotic index Can spread distantly (metastasis) Are named according to the tissues from whichthey arise. • Malignant epithelial tumors: Carcinomas Adenocarcinoma: Ducts or glands • Malignant connective tissue tumors: Sarcomas • Cancers of lymphatic tissue: Lymphomas • Cancers of blood-forming cells: Leukemias #Which cancer originates from connective tissue? Osteogenic sarcoma #Which term is used to describe a muscle cell showing a reduced ability to form new muscle while appearing highly disorganized? Anaplasia #Which statement is true regarding pleomorphic cells? They are a result of anaplasia. #What cellular characteristics are affected by anaplasia?Size Ability to differentiate, Tissue structure Shape

Evading Growth Suppressors

Secretion of growth factors (autocrine stimulation) Increase of growth factor receptors Mutation of the signal from cell surface receptor inthe "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 Mutation in the TP53 gene (tumor-suppressor gene) Suppression of normal apoptosis #Autocrine stimulation is the ability of cancer cells to: Secrete growth factors that stimulate their own growth. #By what process do cancer cells multiply in the absence of external growth signals? Autocrine stimulation

Surgery

Is a definitive treatment of cancers that do not spread beyond the limits of surgical excision. Palliative: Is indicated for the relief of symptoms. In selected high-risk diseases, surgery plays a role in the prevention of cancer. Mutations of the APC gene have close to a 100% lifetime risk of colon cancer: Colectomy. Women with BRCA1/2 mutations have a significantly increased risk of breast and ovarian cancer: Prophylactic mastectomy or bilateral salpingo-oophorectomy or both. Must achieve adequate surgical margins; that is, surgery must get it all. Surgeon provides critical staging information.

Invasion: Local spread

Is a prerequisite for metastasis and the first step in the metastatic process. Cancer often spreads first to regional lymph nodes through the lymphatic system and then to distant organs through the bloodstream. Invasion then requires that the cancer attach to specific receptors and survive in the specific environment.

Cancer Terminology and Characteristics

Is derived from Greek word for "crab"—karkinoma. Is another name for malignant tumor. Cancer is not a tumor. Is an abnormal growth resulting from uncontrolled proliferation; it serves no physiologic function . Is also referred to as a neoplasm: New growth

Cachexia

Is the most severe form of malnutrition. Leads to protein-calorie malnutrition and progressive wasting. Manifestations • Anorexia, early satiety, weight loss, anemia, asthenia ,taste alterations, and altered protein, lipid, and carbohydrate metabolism

Malignant transformation

Is the process during which a normal cell becomes a cancer cell. Heterogeneous mixture of cancer cells Stroma: Tumor microenvironmen

Radiation Therapy

Is used to kill cancer cells while minimizing the damage to normal structures. Ionizing radiation Damages cells by imparting enough ionizing radiation to cause molecular damage to the DNA. Causes irreversible damage to normal cells .• Lifetime radiation dose Brachytherapy Seeds are implanted -Radiation sources, such as small 125I-labeled capsules (also called seeds), can also be temporarily placed into body cavities, a delivery method termed brachytherapy. Brachytherapy is useful in the treatment of cervical, prostate, and head and neck cancers. #Which cancer may be treated with radiation delivered by brachytherapy? Cervical # radiation: Is used to kill cancer cells while minimizing damage to normal structures.

Chromosome translocation

Large changes in chromosome structure Piece of one chromosome is translocated to another chromosome #Burkitt lymphomas designate a chromosome that has a piece of chromosome 8 fused to a piece of chromosome 14. This is an example of which mutation of normal genes to oncogenes? Chromosome translocation

aging

Many common malignancies occur mostly in older age as a result of immunologic functions declining with age. Older persons are predisposed to nutritional inadequacies, and malnutrition impairs immunocompetence. Far-advanced cancer often results in immobility and general debility that worsens with age. #Which statements concerning aging and the occurrence of cancer are true? Decline in immunologic functions Predisposition to nutritional inadequacies, Effects of immobility on the immune system

Epithelial-mesenchymal transition (EMT)

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 #Epithelial-mesenchymal transition (EMT)produces which result? Increased resistance to apoptosi

Activating Invasion and Metastasis

Metastasis: Is the spread of cancer cells from the site of the original tumor to distant tissues and organs through the body. Is a complex process that requires cells to have many new abilities. Spread Survive Proliferate in distant locations Destination must be receptive to growth of cancer Cancer cells secrete protease . Proteases digest the extracellular matrix and basement membranes. Create pathways through which cells can move. Metastatic cells must be able to withstand the physiologic stresses of travel in the blood and lymphatic circulation. Metastatic cells must then survive in a new environment. #What is the role of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in cell metastasis? To develop new blood vessels to feed cancer cells #The most common site of metastasis for a patient diagnosed with prostate cancer is which location? a. Bones #What is the most common route for distant metastasis? blood, lymphatic system

Pain

Pain is generally associated with the late stages of cancer. Pressure, obstruction, invasion of a structure sensitive to pain, stretching, tissue destruction, and inflammation can cause pain. Pain is not the initial symptom of cancer nor does it indication that the cancer has metastasized. #Which statement is true regarding pain and cancer? Pain is generally associated with late-stage cancer.

Tumor Markers

Substances produced by benign or malignant cells. Found on or in a tumor cell, in the blood, in the spinal fluid, or in urine. Hormones Enzymes Genes Antigens Antibodies

Paraneoplastic syndromes

Symptom complexes are triggered by a cancer but are not caused by direct local effects of the tumor mass. Are caused by biologic substances released from the tumor (e.g., hormones) or by an immune response triggered by the tumor. Can be life-threatening.

Carcinoma In Situ

Preinvasive epithelial malignant tumors of glandular or squamous origin. Have not broken through the basement membrane or invaded the surrounding stroma. Not malignant. Three prognoses: Can remain stable for a long time. Can progress to invasive and metastatic cancers . Can regress and disappear #A nurse learns that an individual has benign tumors. What does this mean? The tumors: are encapsulated #Carcinoma in situ is characterized by which changes? Cells remain localized in the glandular or squamous cells. #Carcinoma refers to abnormal cell proliferation originating from which tissue origin? Epithelial cells

Sustained Proliferative Signaling

Three key genetic mechanisms have a role in human carcinogenesis . Activation of proto-oncogenes, resulting in hyperactivity of growth-related gene products(called oncogenes) Mutation of genes, resulting in the loss or inactivity of gene products that would normally inhibit growth (called tumor-suppressor genes) Mutation of genes, resulting in an overexpression of products that prevent normal cell death or apoptosis, thus allowing continued growth of tumors Oncogenes Are mutant genes that, in their nonmutant state, direct protein synthesis and cellular growth. Tumor-suppressor genes Encode proteins that, in their normal state ,negatively regulate proliferation. Are also referred to as anti-oncogenes. Proto-oncogenes Are normal nonmutant genes that code for cellular growth. #Oncogenes are genes that are capable of: Undergoing mutation that directs the synthesis of proteins to accelerate the rate of tissue proliferation #In a normal, nonmutant state, an oncogene is referred to as a: Proto-oncogene

Viruses and Cancer

Tumor associated antigens: oncogenes,antigens from oncogenic viruses, oncofetal antigens, and altered glycoproteins and glycolipids Immune surveillance hypothesis Immunotherapy hypothesis Immunotherapy can be either active or passive. Active: Immunization with tumor antigens to elicitor enhance the immune response against a particular cancer Passive: Injecting the patient diagnosed with cancer with antibodies or lymphocytes directed against the tumor-associated antigen

RAS

Up to one-third of all cancers have an activating mutation in the gene for an intracellular signaling protein called ras. This mutant ras stimulates cell growth even when growth factors are missing. -A point mutation is the alteration of one or a few nucleotide base pairs. This type of mutation can have profound effects on the activity of proteins. A point mutation in the ras gene converts it from a regulated proto-oncogene to an unregulated oncogene, an accelerator of cellular proliferation. #Many cancers create a mutation of ras. ras is a(an): Intracellular-signaling protein that regulates cell growth #The ras gene converts from a proto-oncogene to an oncogene by: Altering one or more nucleotide base pairs

Definition of carcinoma in situ

1. CARCINOMAS: cancers arising from epithelial tissue. 2. If they arise from or form ductal or glandular structures they are called ADENOCARCINOMAS. • Example: a malignant tumor arising from breast glandular tissue is a mammary adenocarcinoma. 3. Sarcoma=cancer arising from mesenchymal tissue (connective tissue, muscle, and bone) • Ex rhabodmyosarcomas (malignant cancer of skeletal muscle) 4. Carcinoma in situ: preinvasive epithelial tumors of glandular or squamous cell origin. • develop incrementally • abnormal growths in epithelial tissue that have atypical cells and an increased proliferation rate • These early stage cancers are localized to the epithelium and have not penetrated the local basement membrane or invaded the surrounding stroma. o Occurs in cervix, skin, oral cavity, esophagus, and bronchus • Glandular epithelium>lesions occur in stomach, endometrium, breast, and large bowel o Breast=ductal carcinoma in situ § Fills mammary ducts • Can have 1 of the following 3 fates o Remain stable for along time o Can progress to invasive and metastatic cancers o Regress and disappear

Know patterns of metastasis

1. Spread of cancer cells from the site of the original tumor to distant tissues and organs through the body 2. Changes in tumor microenvironment initiate the metastatic process and may include stromal cell adaption to increase tumor mass and intratumor hypoxia3 . Epithelial-mesenchymal transition (EMT: Model for transition to metastatic cancer -IL-8 is an effective driver of carcinoma cells into EMT. -Occurs in embryonic development and wound healing and tissue repair -Generally, cells that have transitioned into a mesenchymal-like phenotype have suppressed expression of adhesion molecules with a loss of polarity, increased migratory capacity, and elevated resistance to apoptosis, and have demonstrated the potential to redifferentiate into other cell types.

Tumor-Promoting Inflammation

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 Examples Those with ulcerative colitis for 10 years or more have up to a 30-fold increase in developing colon cancer. Hepatitis B (HBV) or hepatitis C (HCV) increasethe risk of liver cancer. H. pylori increases the risk of stomach cancer A tumor-associated macrophage (TAM) is the key cell that promotes tumor survival. > Develops the capacity to block cytotoxic T cell and natural killer (NK) cell functions. > Produces cytokines that are advantageous for tumor growth and spread. > Secretes angiogenesis factors.

infections

Hospital-acquired (nosocomial) infections increase because of indwelling medical devices, inadequate wound care, and the introduction of microorganisms from visitors and other individuals. #What are the most common causes of nosocomial infections among patients with cancer? Indwelling medical devices, Visitor-introduced microorganisms, Inadequate wound care

viruses have been associated with human cancer:

Human papillomavirus (HPV) Epstein-Barr virus (EBV) Kaposi sarcoma herpesvirus (KSHV or HHV8) Human T-cell lymphotropic virus type I (HTLV-1) Hepatitis B (HBV) Hepatitis C (HCV) Cervical cancer Hepatocellular carcinoma #What is the major virus involved in the development of cervical cancer? Human papillomavirus #cervical cancer:HPV #Kaposi sarcoma:Human herpesvirus (HHV) 8 #Liver cancer:Hepatis B virus (HBV) # Stomach cancer: Helicobacter pylori

Diagnosis and Staging of Cancer

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. Staging using the World Health OrganizationTNM system Tumor (T) - Primary tumor; the number equals size of tumor and its local extent • T0 - Organ free of tumor • T1 - Lesion <2 cm in size • T2 - Lesion 2-5 cm • T3 - Skin and/or chest wall involved by invasion Nodes (N) - Lymph node involvement; a highernumber means more nodes are involved • N0 - No axillary nodes involved • N1 - Mobile nodes involved • N2 - Fixed nodes involved Metastases (M) - Extent of distant metastases • M0 - No metastases • M1 - Demonstrable metastases • M2 - Suspected metastases

anemia

Iron is malabsorbed in individuals with gastric, pancreatic, or upper intestinal cancer. Commonly associated with malignancy, mechanisms of anemia include chronic bleeding (resulting in iron deficiency), severe malnutrition, cytotoxic chemotherapy, and malignancy in blood-forming organs. #What is the cause of anemia in a patient diagnosed with pancreatic cancer? Malabsorption of iron

Gene amplification

Repeated duplication of chromosome 10s or 100s of gene copies mad #n childhood neuroblastoma, the N-myc oncogene undergoes which type of mutation of normal gene to oncogene? Gene amplification

Genomic Instability

Results from epigenetic silencing (modulation of gene). Mutations in caretaker genes that protect genome and DNA repair increase genomic instability and risk of cancer Chromosome instability (CIN) also appears to be increased in malignant cells. May be caused by malfunctions in the cellular machinery that regulates chromosomal segregation at mitosis. Results in a high rate of chromosomal loss, as well as a loss of heterozygosity and chromosomal amplification; each of these events can accelerate the loss of tumor-suppressor genes and the overexpression of oncogenes

Benign tumors

Slow growth Noninvasive Well-differentiated Low mitotic index Does not metastasize Are named according to the tissues from which they arise and include the suffix, -oma .• Lipoma: Fat• Leiomyoma: Smooth muscle #What are characteristics of benign tumors? Benign tumors include the suffix -oma. #Which terms represent the correct nomenclature for benign and malignant tumors of adipose tissue, respectively? Lipoma, liposarcoma #Which statement concerning benign tumors is true? The cells are well-differentiated.