Neoplasia Part 2

Question 1

What are animal models used in cancer research? Why are these animals used? What percentage of people will perish from some sort of cancer?

Answer 1

Animal Models
• Experimentally-induced (Nude Mice) – able to accept grafting: no rejection (no only allografts but also xenografts -> tissue from other species) (No T lymphocytes -> lack thymus)
• Naturally occurring
• some stats of 20-25% of individuals will perish from some sort of cancer.

Question 2

What are epigenetic changes? What else are seen in tumor cells aside from epigenetic changes?

Answer 2

Epigenetic changes: Refers to heritable changes in gene expression in somatic cells resulting from something other than a change in the DNA sequence (most common ones are DNA methylation and histone modification)”.

• DNA mutations, epigenetic changes & chromosomal alterations are also observed in tumor cells.
Some people have genetic predisposition to cancer
Epigenetic changes- No DNA damage but, molecular changes can alter some functions of the tumor.

Question 3

What is carcinogenesis?

Answer 3

Carcinogenesis is a multistep process at both the phenotypic and genetic level -> tumor progression.

Question 4

What occurs to normal cells that cause benign or preneoplastic lesions? What will cause them to potentially become malignant?

Answer 4

• In the presence of a promoter, these initated cells expand to form a preneoplastic lesion or benign tumor. With further genetic and epigenetic alterations, a malignant tumor emerges from a subclone of cells within the benign precursor lesion.

• Initiated cells have growth advantage against other cells if they are in the presence of a premotor.
• Formation of benign tumor can become malignant tumor. If it becomes one, it will have the ability to infiltrate surrounding tissue.

Question 5

Can they cure the individual cancer genes?

Answer 5

No there are too many.

Question 6

What are the 4 classes of normal regulatory genes that are the main targets of genetic damage and play a significant role in carcinogenesis? What happens if you lose repair cells?

Answer 6

• 1. growth-promoting proto-oncogenes
• 2. growth-inhibiting tumor suppressor genes
• 3. genes that regulate programmed cell death (apoptosis), and
• 4. genes involved in DNA repair

If you lose repair cells, you can have abnormalities printed in the genomes.

Question 7

What is the p-53 gene? What does it do?

Answer 7

• p53 gene- cancer cop
◦ Growth inhibiting tumor supressor gene.
• Considered guardian of the genome.

Question 8

What occurs to cells that have dna damage in the presence of P-53 and in the absence?

Answer 8

• Cell exposed to DNA damage -> activated p53 gene -> binds to DNA -> stops cell division until problem is correct/ DNA repaired so damaged cells do not proliferate.
• p21 and GADD45 -> mechanics of cell
◦ If repair fails then cell is normal, if not then apoptosis.

• BAX -> hitman (induces apoptosis)

Cell with loss or damage to P53 then the mutant cells will expand and continue mutating.

Question 9

What are the 8 changes in cell
physiology that together determine malignant phenotype?

Answer 9

1. Self-sufficiency in growth signals (continue to grow)
2. Insensitivity to growth-inhibitory signals (dont respond to inhibitory signals)
3. Evasion of apoptosis (can avoid apoptosis)
4. Defects in DNA repair
5. Limitless replicative potential
6. Sustained angiogenesis
7. Ability to invade and metastasize
8. Ability to escape from immunity and rejection

Question 10

IMPORTANT SLIDE TO GO OVER

Answer 10

Question 11

What is the strongest argument for immune survailences role in cancer? Are the survailence mechanisms as effective as they should be?

Answer 11

• The increase incidence of cancer in immuno-suppressed people
  and animals is the strongest argument for the existence of tumor
  immune surveillance.

• Unfortunately tumor immune surveillance mechanisms are not as
effective as they should be. The reason is that tumor cells have the
capability to develop mechanisms to evade the immune system of
the immunocompetent host.

Question 12

What are tumor antigens? What are the types? and What can they be used for?

Answer 12

• Tumor antigens:
– Tumor-specific antigens (presented by MHC molecules on surface, presented only on tumor cells)
– Tumor-associated antigens (presented on surface of tumor and nontumor cells)

• Tumor antigens can serve as the targets of effective immune
surveillance

• Tumor antigens can be used for diagnosis, monitoring or
immunotherapy
( you can design antibodies against these antigens)

Question 13

What are the major cells involved in immune survailence for cancer cells? What are the main defense mechanism? Is humoral response also effective?

Answer 13

• CD8 + Cytotoxic T lymphocytes (CTLs) are the mayor immune defense mechanism against tumors.
• Natural killer cells (specific type of lymphocytes) and macrophages also play a role. Interferon-gamma (IFN-γ), a cytokine produced by T-cells and NK cells, is a potent activator of macrophages.
• Antibodies against tumor antigens are also part of the defense mechanisms of the host but there is little evidence that humoral immunity is effective against tumors.

Question 14

What are the tumor antigens recognized by CTL or Cytotoxic T lymphocytes?

Answer 14

Tumor antigens recognized by CTLs:
• Product of oncogene or mutated tumor suppressor gene.
• Mutated self protein
• Overexpressed or aberrantly expressed self protein
• Oncovirus ( i.e feline leukemia)

Question 15

What mechanisms can tumors use to evade the immune system?

Answer 15

Mechanisms by which tumors evade the immune system
• Failure to produce tumor antigen
• Mutation in MHC genes or genes needed for antigen processing
• Production of immunosuppressive proteins.

Question 16

What are the macro environmental and microenvironmental causes of tumors?

Answer 16

• 1. Macro-environmental (extrinsic) causes: e.g.: UV light, ionizing radiation, chemical carcinogens, oncoviruses. (Example: FELV cat with lymphoma-> lymphoma caused by FELV (oncovirus))
• 2.Micro-environmental (intrinsic) causes: e.g.: heritable genetic changes, byproducts of normal metabolism including reactive oxygen species.

Question 17

What is an example of an oncovirus?

Answer 17

FELV in cats

Question 18

What is the cause of many of the familial cancer syndromes? What is the role of carcinogens? Are they common?

Answer 18

Many of the familial cancer syndromes are due to mutation
in recessive tumor suppressor genes

Carcinogens are cancer causing compounds

Chemical carcinogens are widespread in the environment.
E.g. The toxin of the bracken fern plant causes urinary
bladder cancer in cattle grazing pastures containing the
plant. • To b a c c o smoke contains potent carcinogens.

Question 19

What is ocular squamous cell carcinoma in cows? What is the cause? who is more susceptible? Is it malignant? What happens if a cow sent to slaughter has a tumor? What is the way to get around thi?

Answer 19

• Ocular squamous cell carcinoma
• Normally cattle that have white faces -> more susceptible to UV light.
◦ Within conjunctiva
◦ Can metastisize.
◦ When sent to slaughter, the entire carcass is condemed.

• “UV radiation causes dimerization and protein cross- links in DNA molecules. Also UV light induces formation of a carcinogen (cholesterol alpha oxide) from natural sterols in unpigmented skin.
• Can also occur in horses.

If they preform enucleation and let it heal carcass will not be condemed at slaughterhouse.

Question 20

What can occur in cats with nonpigemented ears/ faces? What can be the chain of events that lead to the formation of that tumor? Can it metastisize?

Answer 20

• Cats with nonpigmented ears/ faces can get squamous cell carcinoma -> locally invasive
• Usually will develop chronic dermatis, which will cause aplasia, and eventual Squamous cell carcinoma in situ -> which can metastisize.

Question 21

What is one indicator of a squamous cell tumor?

Answer 21

Causes areas of necrosis and ulceration. Can also infiltrate the orbit and cause raised nictated membranes.

Locally invasive, eats away at tissue. :(

Question 22

What are the effects tumors have on the host?

Answer 22

• Focal & hormonal effect
• Paraneoplastic syndromes

Question 23

What is cancer cachexia? What percentage of people get it? Is it common in animals ? Why/ Why not?

Answer 23

• 50 % of people that develop cancer get cancer cachexia -> loss of muscle and fat.
• Not as common in animals, usually diagnosis-> death is short so its hard to see these chronic changes.

Question 24

What proinflamatory cells are involved in the pathogenesis of cancer cachexia?

Answer 24

Cancer cachexia: progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia and anemia” ->
TNF, IL-1, IL-6, IFN-gamma, prostaglandins and PIF (proteolysis inducing factor) are apparently involved in the pathogenesis of cancer cachexia.

Question 25

What percentage of patients (human) with malignant disease have paraneoplastic syndromes?

Answer 25

n humans they occur in approximately 75% (10% if cachexia is not included) of patients with malignant disease.

Question 26

What can paraneoplastic syndromes indicate in patients? Why are they important?

Answer 26

- They may represent the earliest manifestation of an occult neoplasm. – In affected patients they may represent significant clinical problems and may even be lethal.

Question 27

What are examples of paraneoplastic syndromes?

Answer 27

• Examples of paraneoplastic syndromes in domestic animals are: • Cachexia • Hypercalcemia of malignancy. • Hypoglycemia • Thrombotic disease • Peripheral neuropathy • Nodular dermatofibrosis (German Shepherd dogs) • Hypertrophic osteoarthropathy (hypertrophic osteopathy)

Question 28

What is the most frequently observed paraneoplastic syndrome? What is the cause? What should you do if a patient comes in and has high calcium on their bloodwork?

Answer 28

* Most frequently observed paraneoplastic syndrome – primarily in dogs is hypercalcemia. * Due to the production of calcemic humoral substances (parathyroid hormone-related protein, PTHRP) by neoplastic cells from extra- osseous neoplasms. * Hypercalcemia due to osteolysis by skeletal metastases is not a paraneoplastic syndrome If a dog comes in and has high calcium, and then returns and repeat blood shows hypercalcemia, you have to think there is the potential of an occult tumor,

Question 29

What are signs of hypercalcemia?

Answer 29

* Muscle weakness * Cardiac arrhythmia (rare) * anorexia * Vomiting * Renal Failure * Polyuria/ polydipsia

Question 30

What are the differential diagnosis' to rule out with hypercalcemia?

Answer 30

hyperparathyroid, renal failure, hypoadrenocorticism, hypervitaminosis D

Question 31

What are some examples of tumors that include hypercalcemia? 2 most common?

Answer 31

* Apocrine gland carcinomas of anal sacs or lymphosarcomas. * 2 of the most common that present with hypercalcemia.

Question 32

What is hypertrophic osteopathy? What is it a sign of? What occurs? What clinical signs may you see in a patient?

Answer 32

• Hypertrophic osteopathy ◦ Paraneoplastic syndome related to space occupying lesion in the thorax ◦ You will see proliferation of bone in the periosteum. Usually the dog will appear painful with lameness and swollen limbs. Particularly occurs in the long bones.

Question 33

What can occur with chronic spirocercosis?

Answer 33

* 4 year-old dog with a history of chronic regurgitation, vomiting and weight loss associated with esophageal spirocercosis. This caused hypertrophic osteopathy since their was a space occupying lesion found in the esophagus. It was an inflammatory lesion caused by parasite ( spirocera lupi) but then it underwent malignant changes and became a tumor. You can see this highlighted in the next slide. * Ended up having osteosarcoma from this. SPACE OCCUPYING LESION IN THORAX? ESOPHAGUS -\> CAUSED HYPERTROPHIC OSTEOPATHY AND THIS CAUSED TUMOR FORMATION.

Question 34

What is a signs of nodular dermatofibrosis in german shepards? Will their be only one cutaneous lesion? What are they often associated with? What other benign tumors can be paraneoplastic syndrome in german shepards? What phenotype is nodular dermatofibrosis?

Answer 34

* Affected dogs develop multiple benign cutaneous lesions almost always associated with underlying bilateral renal disease: polycystic kidneys, renal cystadenomas or cystadenocarcinomas (most common). Occasionally reported in other breeds. * Fibromas-\> benign tumors, this can be a paraneoplastic syndrome in germanshepards, this can be associated with tumors in the kidneys. * Malignant tumor of glandular epithelium with fluid within the kidney (Renal Cystadenocarcinoma) - Autosomal Dominant

Question 35

what are the ways we can diagnose tumors in the lab?

Answer 35

• Histologic & Cytologic Examination ◦ Clinical data is quite valuable for diagnosis ◦ “Laboratory evaluation can be only as good as the specimen available for examination” • Immunohistochemistry. The availability of monoclonal antibodies has greatly facilitated the identification of cell products or surface markers.

Question 36

What are the advantages of using immunohistochemistry in tumor diagnosis?

Answer 36

• 1. Categorization of undifferentiated malignant tumors ◦ Use of antibodies against specific intermediate (cytoskeletal) filaments: Cytokeratins, Vimentin, Desmin etc. • 2. Categorization of leukemias/ lymphomas 2. Determination of site of origin of metastatic tumors • 3. Determination of molecules that have prognostic or therapeutic significance: ◦ e.g.: determination of estrogen/ progesterone receptors in breast cancer cells -\> receptor positive breast cancers have a better prognosis/ susceptible to anti-estrogen therapy (e.g. Tamoxifen -\> antagonist of the estrogen receptor in breast tissue)

Question 37

What is grading of tumors? What are they classified by? And why is it useful?

Answer 37

• Grading: Gives a semi-quantitative evaluation of the degree of differentiation of the tumor. Cancers are classified from I to IV with increasing anaplasia. • Although histologic grading is useful, histologic appearance not always correlates with biologic behavior.

Question 38

What is involved in the staging of a tumor? Which is more helpful, staging or grading?

Answer 38

• Staging: It is based on the size of the primary tumor, its extend of spread to regional lymph nodes, and the presence or absence of hematogenous metastases. • Staging from a clinical point of view has proved to be more useful than grading.

Question 39

What is the staging system for tumors? What does each part represent?

Answer 39

TNM System: • T= Primary tumor, with increasing size: T1-\> T4. • T0= “in situ” lesion. (Malignant will begin this way) • N: regional LN involvement. • N0= No LN involvement. • N1 to N3 would denote increase number and range of nodes. (increase number by number of nodes involved) • M: Blood-borne metastases. • M0= No blood-borne metastases, • M1 or M2 indicates the presence of blood- borne metastases and some judgment as to their number.