NEOPLASIA VI Tumor Host Interactions

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NEOPLASIA VITumor Host Interactions

• Husni Maqboul, M.D

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Tumor Host Interactions

• Local Effects
• Cancer Cachexia
• Paraneoplastic Syndromes
• Endocrinopathies
• Neuromyopathies
• Osteochondral Disorders
• Vascular Phenomena
• Fever
• Nephrotic Syndrome

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Local Effects

• Tumor Impingement on nearby structures
• Pituitary adenoma on normal gland, Pancreatic
  carcinoma on bile duct, Esophageal carcinoma on
  lumen
• Ulceration/bleeding
• Colon, Gastric, and Renal cell carcinomas

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Local Effects

• Infection (often due to obstruction)
• Pulmonary infections due to blocked bronchi (lung
  carcinoma), Urinary infections due to blocked
  ureters (cervical carcinoma)
• Rupture or Infarction
• Ovarian, Hepatocellular, and Adrenal cortical
  carcinomas Melano-carcinoma metastases

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Cancer Cachexia

• Progressive weakness, loss of appetite, anemia
  and profound weight loss (gt20 lbs.)
• Often correlates with tumor size and extent of
  metastases
• Etiology includes a generalized increase in
  metabolism and central effects of tumor on
  hypothalamus
• Probably related to macrophage production of
  TNF-a and IL-1

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Paraneoplastic SyndromesEndocrinopathies

• Cushings Syndrome
• Adrenal carcinoma (cortisol) more common with
  benign adrenal processes.
• Small cell undifferentiated lung cancer (ACTH)
  released through cleavage of pro-opiomelano-cortin
  gene product.
• Inappropriate ADH syndrome (Hyponatremia)
• Small cell undifferentiated lung cancer
  (vassopressin-like hormone.
• Hypothalamic tumors (vasopressin)

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Paraneoplastic SyndromesEndocrinopathies

• Hypercalcemia (Cancer is the most common cause of
  hypercalcemia by either humoral or metastatic
  mechanisms)
• Squamous cell lung cancer (PTH-like peptide)
• Renal cell carcinoma (prostaglandins)
• Parathyroid carcinoma (PTH)
• Multiple myeloma and T-cell lymphoma (IL-1 and
  perhaps TGF-a)
• Breast carcinoma, usually by bone metastasis

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Paraneoplastic SyndromesEndocrinopathies

• Hypoglycemia - caused by tumor over-production of
  insulin or insulin like activities
• Fibrosarcoma, Cerebellar hemangioma,
  Hepatocarcinoma
• Carcinoid syndrome - Caused by serotonin,
  bradykinin or ?histamine produced by the tumor
• Bronchial carcinoids, Pancreatic carcinoma,
  Carcinoid tumors of the bowel

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Paraneoplastic SyndromesEndocrinopathies

• Polycythemia - caused by tumor production of
  erythropoietins
• Renal cell carcinoma, Cerebellar hemangioma,
  Hepatocarcinoma
• WDHA syndrome (watery diarrhea, hypokalemia, and
  achlorhydria) - caused by tumor production of
  vasoactive intestinal polypeptide (VIP).
• Islet cell tumors, Intestinal carcinoid tumors

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Paraneoplastic SyndromesNeuromyopathies

• Myasthenia - A block in neuromuscular
  transmission possibly caused by host antibodies
  against the tumor cells that cross react with
  neuronal cells or perhaps caused by toxins.
• Bronchogenic carcinoma, Breast cancer
• Carcinomatous Myopathy - probably immune-mediated

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Paraneoplastic SyndromesOsteochondral Disorders

• Hypertrophic Osteoarthropy - clubbing, periosteal
  new bone, and arthritis
• Isolated clubbing occurs in chronic obstructive
  pulmonary disease and in cyanotic congenital
  heart disease, but the full-blown syndrome is
  limited to lung cancer.

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Paraneoplastic SyndromesVascular Phenomena

• Altered Coagulability - caused by the release of
  tumor products
• Migratory Venous Thromboses (Trousseaus sign)
  Pancreatic, gastric, colon, and bronchogenic
  carcinomas particularly adenocarcinoma of the
  lung.
• Marantic endocarditis - Small thrombotic
  vegetations on mitral or aortic valves that occur
  with advanced carcinomas.

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Paraneoplastic SyndromesFever

• Associated with bacterial infections
• Common where blockage of drainage occurs
• Decreased immunity may play a role
• Not associated with infection
• Episodic as in Pel-Ebstein fever with Hodgkins
  lymphoma poor prognostic sign in sarcomas,
  indicates dissemination
• Likely caused by response to necrotic tumor cells
  and/or immune response to necrotic tumor
  proteins.

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Paraneoplastic SyndromesNephrotic Syndrome

• Excessive loss of protein in the urine
• probably caused by damage to renal glomeruli by
  tumor antigen-antibody complexes.

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Host Defense Against TumorsImmune Response to
Tumor Antigens

• Definition - coordinated biologic process
  designed to recognize tumor cells and their
  products and to kill or damage the offending
  cells.

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Host Defense Against TumorsImmune Response to
Tumor Antigens

• Tumor Specific Antigens (TSA) are present only on
  tumor cells and not on any normal cells and can
  be recognized by cytotoxic T-lymphocytes.
• Cancer-Testis Antigens MAGE in melanoma, lung,
  liver, stomach, GAGE, BAGE, RAGE
• Tissue specific antigens MART1 on normal
  melanocytes and melanoma
• Mutational antigens products of mutated RAS,
  TP53, ß-catenin
• Overexpressed antigens (not recognized normally
  because of low concentration ) HER-2 protein in
  breast carcinoma
• Viral antigens HPV, EBV
• Mucins underglycosylation of tumor mucin
  product reveals epitopes that were covered by
  carbohydrates (MUC-1)

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Host Defense Against TumorsImmune Response to
Tumor Antigens

• Tumor Associated Antigens (TAA) are not unique to
  tumors.
• Tumor-associated carbohydrate antigens
• Oncofetal antigens
• Expressed in embryogenesis, but not in adult
  tissue ( CEA, AFP)
• Differentiation-specific antigens
• CD10 on neoplastic and normal B-cells
• PSA on normal and neoplastic prostatic
  epithelial cells
• Not helpful for tumor rejection but useful for
  diagnosis and therapy.

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Evidence for immune response to tumors-I

• Immune surveillance a constant monitoring
  process aimed at eliminating emerging cancers.
• Evidence for immune response to tumor
• 1) Infiltrate of lymphocytes and macrophages
  associated with better prognosis in many tumors.
  
• 2) Peripheral blood NK activity correlates with
  survival.
• 3) Peripheral blood lymphocytes counts fall as
  cancer overwhelms host patients develop anergy
  to skin tests.

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Evidence for Immune Response to Tumors-II

• 4) Non-specific vaccines can stimulate
  macrophages and improve prognosis. IFN-g and
  IL-2 can stimulate NK cells and improve outcome.
• 5) High incidence of some tumors in
  immunosupressed individuals.
• 6) Spontaneous regression in some tumors.
• 7) Experimental animals cured of tumor reject
  rechallenge by the tumor.

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Mechanisms of Immunity to Tumors-I

• Cytotoxic T lymphocytes (CTL) - that are
  sensitized to TSA and perhaps other tumor
  antigens kill tumor cells.
• Helper T lymphocytes - release IL-2 and IFN-g
  which stimulate CTL, macrophages, NK cells and B
  lymphocytes. They also produce TNF-a.
• Natural Killer (NK) cells - can attack tumor
  cells directly without antibody coating or by
  Antibody Dependent Cell Cytotoxicity (ADCC)
  utilizing the Fc receptor on the NK cells.

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Mechanisms of Immunity to Tumors-II

• Killer Macrophages - activated by IFN-g
  elaborated by Helper T lymphocytes. Participate
  in ADCC and can lyse tumor cells through release
  of TNF-a.
• B lymphocytes/Plasma cells - Produce antibody
  directed against tumor antigens that can kill
  tumor cells by complement activation.
• Lymphokine Activated Killer (LAK) Cells - CTL and
  NK cells from the tumor activated by IL-2 and
  IFN-g. Tumor infiltrating lymphocytes (TIL) are
  CTL sensitized to the tumor that can be expanded
  in vitro and reintroduced to the patient.

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Mechanisms of Tumor Resistance to Immune
Response-I

• Many human tumors are weakly antigenic
• Reduced expression of HLA-I
• Elimination of strongly immumogenic clones
• Lack of costimulation
• Blocking antibodies obscure tumor associated
  antigens (TAA).
• Shed tumor antigens tie up receptors on ADCC
  mediating cells.
• Large tumor burden produces so much TAA that
  tolerance develops.

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Mechanisms of Tumor Resistance to Immune
Response-II

• Antigenic evolution occurs as tumor progresses.
• Genetic inability of host to respond to certain
  antigens.
• Immunosuppression
• Some tumors produce TGF-ß
• Increase of suppressor T-cells
• Protein calorie malnutrition resulting from the
  tumor reduces immune response.