Biology of Cancer and Tumor Spread

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Biology of Cancer and Tumor Spread

• Chapter 9

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• Tumor 1922
• it is tissue overgrowth that is independent of
  the laws governing the remainder of the body
• neoplastic overgrowth serves no useful purpose
  to the organism

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• Cancer
• Modern uncontrolled clonal proliferation of
  cells that can arise from virtually any cell type
  in the body
• Derived from the Greek word for crab karkinoma
  Hippocrates (460 370 BC)
• Malignant tumors
• Tumor
• Also referred to as a neoplasm new growth

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Clonal Proliferation of a Single CellStorm
Troopers Star Wars
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Benign vs. Malignant Tumors
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• Classification Nomenclature
• Benign
• Named according to the tissue from which they
  arise, and includes the suffix - oma
• Lipoma
• Glioma
• Leiomyoma
• Chondroma

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• Classification Nomenclature
• Malignant tumors
• Named according to the cell type from which they
  arise
• Epithelial tissue carcinoma
• Ductal or glandular epithelium adenocarcinoma
• Example mammary adenocarcinoma
• Connective tissue sarcoma
• Example rhabdomyosarcoma
• Lymphatics lymphomas
• Blood forming cells leukemia

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• Classification Nomenclature
• Carcinoma in situ (CIS)
• Preinvasive epithelial malignant tumors of
  glandular or
• squamous cell origin that have not broken through
  the basement membrane or invaded the surround
  stroma
• Cervix, skin, oral cavity, esophagus and bronchus
  (epithelium)
• Stomach, endometrium, breast, large bowel
  (glandular)

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• Stages of Cancer Spread
• important component to diagnosis and treatment
• Physical findings
• Laboratory tests histological/biochemical/geneti
  c
• Imaging studies

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Breast Cancer
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• Cancer Cells
• Transformation
• Autonomy
• Cancer cells independent from normal cellular
  controls
• Anaplasia
• Loss of differentiation (specialization and
  organization)
• without form - pleomorphic

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• Cancer and Stem Cells
• Stem cells self-renew
• Cell divisions create new stem cells
• Stem cells are pluripotent
• Ability to differentiate into multiple different
  cell types

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Stem Cell
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• Tumor Markers (DNARNAProteins)
• Tumor cell markers (biologic markers) are
  substances produced by cancer cells or that are
  found on tumor plasma cell membranes, in the
  blood, CSF, or urine
• Hormones
• Enzymes
• Genes
• Antigens
• Antibodies

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Cancera genetic disease

• DNA RNA Proteins
• normal regulated growth
• DNA RNA Proteins
• 1. Plasma membrane
• 2. Intracellular enzyme system
• 3. Hormones
• unregulated growthcolonal proliferation
• multiple mutations

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Cancera genetic disease

• DNA RNA
  Proteins(antigen)
• Example
• EarlyCDT-Lung (Oncoimmune)-blood test
• 6 cancer associated antigens (p53, 5)
• Autoantibodiesagainst abnormal proteins
• Medscape Medical News Sept 20,2010

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• Tumor Markers Table 9-2
• Used
• Screen and identify individuals at high risk for
  cancer(CA-125, PSA, CEA, Bense Jones protein)
• Diagnose specific types of tumors
• Observe clinical course of cancer

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Types of Genetic Lesions in Cancer

• Point mutation
• Subtle alterations (insertions, deletions)
• Chromosome changes (aneuploidy and loss of
  heterozygosity)
• Amplification
• Gene silencing
• Exogenous sequences (tumor viruses)

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• Genetic Basis of Cancer
• Cancer-causing mutations
• Disease of aging (more mutation over time)
• Clonal proliferation or expansion
• Mutation leads to a Darwinian
• Survival advantage
• (? growth or ? apoptosis)
• Multiple mutations are required before cancer can
  develop

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• Oncogenes and Tumor-Suppressor Genes
• ProtoOncogenes/Oncogenes
• Mutant genes that in their non-mutant state
  direct protein synthesis and cellular growth
  (acceleration)
• Tumor-suppressor genes
• Encoded proteins that in their normal state
  negatively regulate proliferation
• Also referred to as antioncogenes (put the brakes
  on)

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• Types of Mutated Gene 7 mechanisms
• Secretion of growth factors (autocrine
  stimulation)
• Increased growth factor receptors (HER2/neu)
• Signal from cell-surface receptors is mutated to
  the on position
• Mutation in the ras intracellular signaling
  protein (cell growth without growth factors)
• all lead to increase growth

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Types of Mutated Genes
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• Types of Mutated Genes7 mechanisms
• Inactivation of Rb tumor suppressor
• Activation of protein kinase that drive the cell
  cycle (intracellular signaling)
• Mutation in the p53 gene ( apoptosis)

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Types of Mutated GenesBowel Cancer
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• Angiogenesis
• Growth of new blood vessels
• Advanced cancers can secrete angiogenic factors
  (VEGF)

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• Telomeres and Immortality
• Body cells are not immortal and can only divide a
  limited number of times (multicopy repeat DNA
  sequence)
• Telomeres are protective cap on each chromosome
  and are held in place by telomerase (germ cells)
• Telomeres become smaller and smaller with each
  cell division- somatic cells
• Nobel Prize 2009Blackburn, Greider, Szostak

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Telomeres and Immortality
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• Oncogenes and Tumor-Suppressor Genes
• Oncogenes
• Mutant genes that in their non-mutant state
  direct protein synthesis and cellular growth
  (acceleration)
• Tumor-suppressor genes
• Encoded proteins that in their normal state
  negatively regulate proliferation
• Also referred to as antioncogenes (put the brakes
  on)

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• Mutations of Normal Genes ? Cancer Genes
• Point mutation (most common)
• Change of one or a few nucleotide base pairs
• ras gene (pancreatic, colon)
• Chromosome translocation
• A piece on one chromosome is transferred to
  another
• t(814) Burkitt Lymphoma
• t(922) chronic myeloid leukemia (Philadelphia
  chromosome 1960)

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• Mutations of Normal Genes ? Cancer Genes
• Chromosome amplification
• Duplication of a small piece of chromosome (DNA)
  over and over
• Result in ? expression of an oncogene
• N-myc oncogene _at_ 25 amplification
• Childhood neuroblastoma poor prognosis

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Mutation of Normal Genes
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• Mutations of Normal Genes ?Cancer Genes
• Tumor-suppression genes(inherited)
• Unregulated cellular growth (put on the brakes)
  Rb gene (inactivated) ? retinoblastoma, lung,
  breast, bone
• Two hits or mutations to inactivate the genes

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• Mutations of Normal Genes ? Cancer Genes
• Loss of heterozygosity
• Loss of a chromosome region in one chromosome
• Unmasks mutation in the other locus of a tumor
  suppression gene

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• Mutations of Normal Genes ? Cancer Genes
• Gene silencing
• No mutation or change in DNA sequence
• Whole regions of chromosomes are shut off while
  the same regions in other cells remain active
• Shuts off critical tumor suppression genes

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Mutation of Normal Genes Tumor Suppression Genes
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• Mutations of Normal Genes ? Cancer Genes
• Caretaker genes(inherited)
• Encode for proteins that are involved in
  repairing damaged DNA (UV or ionizing radiation,
  chemicals and drugs)
• Loss lead to increase mutation rates
• Chromosome instability
• Increase in malignant cells
• Results in chromosome loss, loss of
  heterozygosity and chromosome amplification
• Loss of tumor suppression genes with
  overexpression of oncogenes

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• Genetics and Cancer-Prone Families
• Somatic cells most cancers
• Exposure to mutagen
• Defect in DNA repair
• Not inherited
• Germ line cells (sperms and eggs)
• Vertical transmission of cancer causing genes
• Tumor suppression and caretaker genes
• One mutant allele (mom or dad), loss of
  heterozygosity in some cells ? tumors

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• Viruses and Cancer
• Implicated
• Hepatitis B C viruses
• Epstein-Barr Virus (EBV)
• Kaposis Sarcoma Herpes Virus (KSHV)
• Human Papillomavirus (HPV)
• Human T cell Leukemia Lymphoma Virus (HTLV)
• 80 virus-linked cancers

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• Bacterial Causes of Cancer
• Helicobacter pylori
• Chronic infections associated with
• Peptic ulcer disease
• Stomach carcinoma
• Mucosa-associated lymphoid tissue lymphoma

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• Immunity and Cancer
• Surveillance nonself
• Viral-induced cancers
• Immune defect
• HIV /immunosuppressants
• ? viral cancers
• Organ transplant immunosuppression little or
  no ? in prevalent cancers
• So ? ?

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• Immunity and Cancer
• Chronic inflammation complex
• Cytokine release form inflammatory cells may
  promote growth
• Free radicals
• Mutation promotion
• ? response to DNA damage
• Diseases
• Ulcerative colitis 30x ?
• Liver HBV/HBC - ? risk
• Lung cancer chronic asthma ?66

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• Cancer Progression and Metastasis
• Metastasis a defining characteristic of
  cancer
• Localized may be cured(in situ)
• Breast 5 year survival gt 90 - local
• 5 year survival lt 3 - metastatic
• Pattern of spread
• Vascular, lymphatic and natural tissue planes
• Selectivity
• Breast to bone, not kidney or spleen
• Lymphomas to spleen, not bone

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• Distant Metastasis
• Cancer cells must detach(invade) and migrate from
  its primary location
• Survive passage through the body
• Attach, invade and multiply while stimulating
  angiogenesis
• Thus
• 1. Vast majority of cancer cells do not have
  the
• ability to form metastasis
• appropriate cancer seed and a permissive soil

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• Clinical Manifestations of Cancer
• Pain
• Little or no pain is associated with early stages
  of malignancy
• Influenced by fear, anxiety, sleep loss, fatigue
  and overall physical deterioration
• Mechanism
• Pressure, obstruction, invasion of sensitive
  structures, stretching of visceral surfaces,
  tissue destruction and inflammation
• Priorities of treatment
• Control rapid and complete (patient)
• Prevention of recurrence

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• Clinical Manifestations of Cancer
• Fatigue
• Tiredness, weakness, lack of energy, exhaustion,
  lethargy, inability to concentrate, depression,
  sleepiness, boredom, lack of motivation and
  ? mental status
• Most frequently reported symptom
  cancer/treatment
• Mechanism poorly understood

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• Clinical Manifestations of Cancer
• Cachexia
• Most severe form of malnutrition
• Present in 80 of cancer patients at death
• Includes
• Anorexia, early satiety, weight loss, anemia
  asthenia, taste alterations and altered protein,
  lipid and carbohydrate metabolism
• Mechanism multifactoral
• Hormones (leptin)
• Neuropeptides
• Pro-inflammatory cytokines

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Cachexia
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• Clinical Manifestations of Cancer
• Anemia
• Decreased amount of hemoglobin in the blood
• Mechanisms
• Chronic bleeding resulting in Fe deficiency,
  severe malnutrition, medial therapies or
  malignancy in blood forming organs
• Suppression of erythropoietin on the bone marrow
• rHuEPO

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• Clinical Manifestations of Cancer
• Leukopenia and thrombocytopenia
• Direct tumor invasion to the bone marrow
• Chemotherapy toxic to bone marrow
• Infection
• Risk increases when the absolute neutrophil and
  lymphocyte counts fall
• ANC WBC x ( neurophils bands), if lt 1000
  protective ? isolation)
• Table 10-3 Review

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• Clinical Manifestations of Cancer
• Paraneoplastic syndromes
• Symptom complex unexplained by local or distant
  spread of the tumor or by the effects of hormones
  released by the tissues from which the tumor
  arose
• 10 of individuals
• Earliest symptoms of an unknown cause
• May represent serious and life threatening
  problems
• May mimic cancer progression and interfere with
  appropriate treatment.
• Table 10-4 Review

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• Side Effects of Cancer Treatment
• targeting the most rapidly growing cells
• Gastrointestinal tract
• Oral ulcers, malabsorption and diarrhea
• Nausea and vomiting ? antiemetic therapy
• Supplemental nutrition (enteral or parenteral)
• Bone marrow
• Anemia ?RBC with fatigue
• Platelets bleeding
• White blood cells infection (ANC)