April 1 1930

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April 1 1930

• Leo Hartnett of the Chicago Cubs broke the
  altitude record for a catch by catching a
  baseball dropped from the Goodyear blimp 800 feet
  over Los Angeles.

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Limitless Replicative Potential Telomerase

• Passage through the cell cycle results in a
  shortening of telomeres, once a certain length is
  attained the cell enters senescence. Telomeres
  are lengthened by telomerase an enzyme that is
  inactive in most somatic cells. 90 of human
  tumor cells have shown reactivation of telomerase
  with resulting replicative immortality

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Development of Sustained Angiogenesis

• Tumor survival at a size gt than 1-2 mm requires
  the induction of angiogenesis. Tumors elaborate
  a number of vasculogenesis factors (PDGF, VEGF,
  FGF etc.). Normal cells also produce
  anti-angiogenic factors (angiostatin
  endostatin) loss of this function may also
  promote tumor angiogenesis. Blocking
  angiogenesis is being studied as an avenue of
  intervention.

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Invasion Metastasis

• Invasion metastasis involves a sequence of
  steps that may be interrupted at any stage by
  host factors. The ability to invade and
  metastasize requires a number of capabilities
  resulting form the accumulation of functional
  abnormalities. This is supported by the clinical
  observation that metastatic disease tends to be a
  function of the duration of neoplastic disease
  however some tumors routinely develop metastasis
  early in the course of the disease.

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The steps in metastasis

• Detachment of tumor cells cadherins are surface
  glycoproteins involved in cell-cell adhesion
  down regulation of cadherin production has been
  identified in several carcinomas.
• Attachment to matrix components allow tumor cells
  to adhere to ECM components
• Degradation of extracellular matrix after
  attachment tumor cells secretion of matrix
  proteolytic enzymes particularly type IV
  collagenases (basement membrane collagen) is
  correlated with metastatic capability.

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• 4. Migration of tumor cells
• 5. Vascular dissemination of tumor cells
  emboli of tumor cells from aggregates with
  lymphocytes platelets, this affords some
  protection from anti-tumor directed T-cells.
• 6. Tissue homing, adhesion and invasion some
  tumors show a distinct preference for metastatic
  involvement. Local tissues may be involved by
  direct extension, however the predilection of
  tumors for certain tissue is due to organ
  specific receptor of the tumor emboli.

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Dysregulation of Cancer-Associated Genes

• In addition to mutational activation of oncogenes
  or loss of function of tumor suppressor genes,
  large chromosomal changes as well as epigenetic
  changes can induce malignancy.
• Chromosomal Changes
• Chromosomal translocations inversions can
  activate proto-oncogenes or disrupt tumor
  suppression by removing these genes from their
  normal regulatory environment or the formation of
  hybrid genes that affect transformation and
  malignant characteristics.

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• Gene Amplification
• Amplification of normally suppressed
  proto-oncogenes may induce tumor-genesis by
  overwhelming the ability of the cell to respond
  with adequate tumor suppressor molecules
• Epigenetic Changes
• Methylation of DNA is a mechanism of control of
  gene expression (usually turning them off),
  methylation in the promoter region of tumor
  suppression genes has been identified in some GI
  malignancies. Directed methylation/demethylation
  is being investigated as a therapeutic method.

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MOLECULAR BASIS OF MULTISTEP CARCINOGENESIS

• Normal cell proliferation is controlled by a
  number of gene categories
• Proto-oncogenes,
• Tumor suppressor genes
• Apoptosis regulating genes,
• It is influenced by a host of other genes.
• Alteration of one gene or category of gene is
  insufficient to produced uncontrolled growth.
• A number of clinical observations support a
  multi-step mechanism for carcinogenesis.
• Analysis of most human cancers reveals multiple
  genetic alterations to several proto-oncogenes
  and the loss of two or more suppressor genes.
• The sequence for cumulative mutations has been
  described for colorectal cancers.

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Adenomatous poliposis coli
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Tumor Progression Heterogeneity

• Over time there is the tendency for tumors to
  become more aggressive and acquire malignant
  capabilities (malignant progression).This is
  often associated with increasingly abnormal
  histology (malignant degeneration).
• This incremental acquisition of capabilities is
  reflective of the accumulation of mutations.
• Although tumors are the product of a single
  transformed cell when detected malignant tumors
  are composed of subpopulations of cells with
  different combinations of capabilities.

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Carcinogenic Agents Their Cellular interactions

• Agents causing genetic damage leading to
  transformation include
• Chemical carcinogens
• Radiant energy
• Oncogenic microbes

Smokeless Tobacco
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Chemical carcinogenesis

• 2 Stages
• 1. Initiation
• Initiation refers to the induction of certain
  mutations in cell which under certain conditions
  allow them to be transformed (initiation does not
  transform cells). The targets of initiation are
• Proto-oncogene
• Tumor suppressor genes
• Apoptosis regulating genes
• DNA repair genes
• Initiators generally fall into 2 categories
• Direct acting carcinogens
• Procarcinogens which require metabolic activation
  by the host to become active, this most often
  involves microsomal cytochrome P-450 oxygenases.

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Chemical carcinogenesis

• But mutation alone is not sufficient to produce a
  tumor, the mutated cell must proliferate, a
  non-dividing cell will not make a tumor!
• 2. Promotion
• Tumorogenesis requires proliferation of the
  initiated cell occasionally the initiating
  substance may also induce promotion. Promotion
  often involves normal proliferative signals
  directed at a number of cells (initiated cells
  may be more sensitive to normal signals or
  sensitive to normally non-proliferative signals)
  and the initiated cell responds with poorly
  controlled proliferation which results in the
  acquisition of a larger number and more diverse
  mutations leading to overt malignancy.

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Initiation Promotion in Carcingenesis

• Example Skin cancer
• UV exposure induces a mutation in DNA repair
• Sun exposure resulting in skin damage also
  elicits reparative proliferation which in the DNA
  repair deficient cell allows the development of
  more mutations eventually producing a neoplastic
  cell.
• A neighboring muscle cell with the same DNA
  repair defect does not receive a proliferative
  signal so never develops into a malignancy.

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Chemical Carcinogens

• Alkylating agents they alkylate genetic
  material resulting in cell death, they are used
  as anti-neoplastic drugs and immune suppressants
  they have been shown to increase the risk of
  tumors, particularly lymphoid leukemic
  neoplasms.
• Polycyclic aromatic hydrocarbons particularly
  potent carcinogens found in cigarette smoke.
• Naturally occurring carcinogens Aflatoxin B1
  produced by Aspergillus flavus fungi (favors
  grains peanuts) is a potent hepatocarcinogen
  associated with liver cancer in China Africa.
• Nitrosoamines amides Ingested as nitrates or
  derived from digested proteins may contribute to
  gastric cancer. Nitrites are used to cure meats
  (hot dogs, pastrami, etc.) they are also produced
  from proteins exposed to high temperatures (we
  call this cooking).

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Radiation Carcinogenesis

• UV Rays
• Natural UV radiation especially UVB acts as both
  initiator through the production of pyrimidine
  dimers promoter for skin cancers.
• In animal models UV exposure has been associated
  with immuno-suppression.
• Ionizing Radiation
• Electromagnetic particulate radiation are
  mutagenic both through direct DNA damage and by
  the production of free radicals.
• Lung cancer in uranium miners
• Thyroid cancer in those treated with head neck
  radiation
• Skin cancer myeloid leukemias in radiologists

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Microbial Carcinogenesis

• Viral and bacterial infections are associated
  with an elevated risk of some cancers.
• Oncogenic DNA Viruses
• Oncogenic viral DNA integrates into host cell
  genomes, often this integration is incomplete so
  the virus is unable to complete a lytic cycle and
  remains in the host genome. Viral genes
  transcribed early in the viral life cycle are
  important for transformation and expressed in
  transformed cells.

Human Papillomavirus
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• Human papillomavirus (70 genetically distinct
  types)
• Types 1, 2, 4, 7 are associated with benign
  squamous papilomas (warts)
• HPV 16 18 associated with cervical cancer in
  gt90 of cases and CIS
• HPV-6 -11 cause genital warts (low malignant
  potential)
• Hepatitis B virus
• HBV is closely associated with a significantly
  increased risk of liver cancer in many parts of
  the world. HBV infection produces a protein that
  blocks p53 function, activates several
  proto-oncogene and hepatocyte injury stimulates a
  reparative proliferation. The combination of
  increased cell division and injury to mitotic
  control mechanisms logically promotes the risk of
  generating a transformed hepatocyte clone.
• Epstein-Barr virus
• Burkitts lymphoma a cancer of the lymphatic
  system (in particular, B lymphocytes). The most
  common malignancy of children in equatorial
  Africa this area. Children affected with the
  disease often also had chronic malaria which is
  believed to have reduced resistance to
  Epstein-Barr virus allowing it to take hold. The
  disease characteristically involves the jaw or
  other facial bone, distal ileum, cecum, ovaries,
  kidney or the breast.

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• Duct Tape More Effective than Cryotherapy for
  Warts
• American Journal Of Family Practice 2/01/2003

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Host Defenses Against Tumors

• Tumors often possess unique cell surface markers
  and may be identified by an immune surveillance
  system. This may offer little help in tumor
  defense as the genetic instability of a tumor may
  result in a selection of non-immunogenic tumor
  cells (cancer immunoediting).
• Tumor antigens These may be categorized into 2
  types
• 1. Tumor-specific antigens These have been
  identified in some human tumors, they are
  composed of unique tumor-derived peptides that
  are presented on the cell surface by Class I MHC
  molecules and recognized by T-cells. This can
  result in sensitization of the host and elicit an
  immune response which may range from mild to
  severe with significant tumoricidal effects.
• 2. Tumor-associated antigens are antigens
  normally expressed on nonneoplastic cells that
  are produced in larger quantities with the clonal
  expansion of tumor growth, while they do not
  elicit an immune response they may be used to
  monitor treatment progress and the development of
  recurrence or metastatic disease.

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Effects of the Tumor on the Host

• 1. Related to location both benign malignant
  tumors are space occupying lesions that can
  interfere with normal function
• 2. Hormone production Tumors of endocrine
  glands, malignant or more often benign can
  produce hormone products under little or no
  normal control.
• 3. Cancer cachexia A sinister combination of fat
  and muscle wasting that is simultaneously
  debilitating and impairs the ability to tolerate
  therapeutic interventions. It is associated with
  a fundamental metabolic change leading to
  increased fat metabolism, decreased fat storage,
  the production of TNF (cachectin) by macrophages
  and proteolysis inducing factor (PIF) that
  increased the catabolism of protein fat.
• 4. Paraneoplastic syndromes Symptoms not
  directly related to tumor growth but of the
  production of hormone by tumors. Tumors may
  acquire the capability to produce hormone-like
  proteins which function on normal cells.
  Hypercalcemia may result from the production of
  PTH-like proteins or may also result from bony
  destruction by metastatic disease (not considered
  a paraneoplastic effect). Small cell lung cancer
  can be associated with the production of ACTH,
  ADH like substances
• 5. Thrombotic diatheses These result from the
  production of thrombotic substances by tumor
  cells and may manifest as thrombotic disorders
  including DIC, migratory thrombophlebitis or
  nonbacterial thrombotic endocarditis.

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Grading Staging of Tumors

• Grading involves the histologic examination of
  tumor tissue and is based on the degree of
  differentiation of the tissue, grading is usually
  based on a I to IV scale (higher is more
  abnormal) the particulars of grading systems are
  type specific. Tumors may show inconsistencies
  in grading depending on the area sampled (tumor
  heterogeneity) and the grade may change as the
  tumor grows (malignant degeneration).
• Staging is based on the anatomic extent of the
  tumor. This is based on primary tumor size (T),
  nodal involvement (N) and the location extent
  of Metastatic involvement (M). Treatment options
  and prognosis are based on staging.

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Grading Staging of Tumors

• A Generalized Scheme
• T ((0),1-4) size or direct extent of the primary
  tumor
• N (0-3) degree of spread to regional lymph nodes
  
• N0 tumor cells absent from regional lymph nodes
• N1 tumor cells spread to closest or small number
  of regional lymph nodes
• N2 tumor cells spread to an extent between N1
  and N3.
• N3 tumor cells spread to most distant or
  numerous regional lymph nodes
• M (0/1) presence of metastasis
• M0 no distant metastasis
• M1 metastasis to distant organs (beyond regional
  lymph nodes)
• Treatment options and prognosis are based on
  staging.
• Some particular cancer types have there own
  staging schemes
• Colon cancer- Dukes system
• Lymphoma- Ann Arbor system