lectures 37-39

Question 1

Distinguish benign and malignant tumors by their characteristics and by naming convention.

Answer 1

malignant tumors:
- less differentiated
- invasive
- metastatic
- large
- poorly demarcated and differentiated
- rapidly growing with hemorrhage and necrosis
- locally invasive

benign tumors:
- small
- well demarcated
- slow growing
- noninvasive
- non-metastatic
- well differentiated

naming:
- benign tumor: adding the suffix -oma to the parenchymal tissue type (adenoma, osteoma, neuroma, glioma, hemangioma, leiomyoma)
- carcinoma: malignant tumor of epithelial tissue (adenocarcinoma)
- sarcoma: malignant tumor of connective, muscle, and endothelial tissues (osteosarcoma, leiomyosarcoma, hemangiosarcoma)
- leukemia: malignant tumor of blood cells
- blastoma: malignant tumor of precursor cells (neuroblastoma, glioblastoma, retinoblastoma)

Question 2

Describe characteristics of cancer cells.

Answer 2

loss of cell differentiation (anaplasia)

genetic instability (aneuploidy, point mutations)

growth factor independence

loss of cell density-dependent inhibition (lack of contact inhibition)

anchorage independence (remain viable and multiply without normal attachments)

faulty cell-to-cell communication

unlimited life span

antigen expression (molecules identified as foreign or tumor antigens, cancer biomarkers)

abnormal production of proteins, hormones, etc. (enable invasion and metastatic spread)

cytoskeletal changes

Question 3

Explain the differences in staging and grading of cancers.

Answer 3

Grading:
- determined by microscopic examination or tumor cell morphology
- samples obtained by biopsy
- largely qualitative in nature
- based on the differentiation state and the number of mitoses of the tumor
- Grade X- grade cannot be assessed (undetermined grade)
- Grade I- well differentiated (low grade)
- Grade II- moderately differentiated (intermediate grade)
- Grade III- poorly differentiated (high grade)
- Grade IV- undifferentiated (high grade)

Staging:
- based on the size of the primary lesion (T), extent of spread to lymph nodes (N) and the presence or absence of metastasis (M)
- largely quantitative in nature
- of greater clinical value
- the tumor, node, metastasis (TNM) system: T0-4, N0-3, M0 or M1 (ex. T3N1M0)

Question 4

Distinguish two major classes of genes that are targets of genetic damage during carcinogenesis.

Answer 4

oncogenes: genes that encode proteins that promote cancer
- altered genes that drive cancer
- translocation that makes a protein with a new function
- mutation that makes a more active version of protein
- gene duplication and over-expression of a normal protein involved in cell growth
- dominant alterations
- normal version is called (proto-oncogene)
- BCR-ABL protein results as a chromosomal translocation; it produces a hyperactive kinase that drives proliferation in leukemia

tumor suppressor genes: genes that encode proteins that inhibit cancer
- most tumor suppressors are recessive and need homozygous deletion/mutation on both alleles
- one-hit vs. two-hit
- heterozygous mutations in tumor suppressor genes can be inherited, and families show increases susceptibility to cancer

Question 5

Explain the “two-hit” hypothesis for tumor suppressor genes.

Answer 5

• two mutations required for retinoblastoma are the mutations in both alleles of the same gene (RBI), which is a tumor suppressor
• the carriers already have a recessive genetic mutation in one allele; one more mutation on the other allele (one-hit) can cause cancer
• non-carriers require mutations on both alleles (two-hit) to develop cancer
• assumption that retinoblastoma requires two mutations
• originally postulated purely mathematically based on the incidence of retinoblastoma by Alfred Knudsen in 1971
  -the hypothesis accurately predicts the number of cases of the cancer over time in hereditary and nonhereditary retinoblastoma

Question 6

Explain the mechanism of how each risk factor increases cancer risk.

Answer 6

age:
- cancers frequently require multiple mutations and often take 20+ years to develop
- two common causes: accumulation of somatic mutation, decline in immune function

environmental factors:
- the time required for cancer development decreases with the increased mutation rate
- smokers develop lung cancer much faster than non-smokers
- carcinogens, UV radiation, ionizing radiation
- carcinogens are agents that can induce the genetic changes characteristic of tumors’ most react with DNA leading to mutations

genetics:
- inherited mutations in tumor suppressor genes
- many are DNA repair genes
- BRCA1/2: DS break repair, ovarian and breast cancer
- XP (xeroderma pigmentosum): nucleotide-excision repair; skin cancer
- ATM (ataxia telangiectasia): DS break repair; lymphoma and leukemia
- BLM (Bloom’s syndrome): DNA helicase; various cancers

inflammation:
- chronic inflammation results in persistent regenerative cell proliferation of hyperplasia and DNA damage by ROS and nitrogen species
- long unhealed skin wounds characterized by persistent damage can lead to skin cancer
- cirrhosis of the liver can lead to hepatocellular carcinoma
- chronic gastritis due to long-standing H. pylori infection can lead to gastric cancer
- chronic ulcerative colitis can lead to colorectal cancer

viruses:
- integration into the genome (retroviruses) can cause modulation of oncogenes or tumor suppressor genes
- chronic inflammation caused by HBV and HCV increases the risk of liver cancer
- viral proteins may alter cellular pathways (inactivation of tumor suppressors, disruption of the normal cell-cycle control)

Question 7

Explain how the six hallmarks contribute to the pathology of cancers.

Answer 7

1. self sufficiency in growth signals:
   - activation of kinase signal transduction pathways that respond to mitogenic signaling (growth factors)
   - growth factor receptors are RTKs
   - activation of an RTK (gain of function or amplification)
   - activation of oncogenes
   - inactivation of tumor suppressors
2. resistance to growth inhibitory signals:
   - cancer may arise through loss of expression (mutation) of growth inhibitory proteins (tumor suppressors)
3. evading apoptosis:
   - disruption of apoptotic pathways prevents cell death upon DNA damage or cell cycle checkpoint activation
   - tumor suppressors: p53, P21, BAX
4. limitless replicative potential:
   - normal cells can divide only 40-60 times (Hayflick limit)
   - telomere shortening leads to chromosomal abnormalities (loss of genes near the end of chromosomes) and cell death
   - tumor cells over-express telomerase, leading to cell immortalization
5. sustained angiogenesis:
   - tumor cells can trigger angiogenesis (neovascularization)
   - solid tumors cannot grow beyond 1-2 mm diameter without blood supply (deficient in oxygen and nutrients, unable to get rid of metabolic waste)
   - tumor cells produce VEGF to promote angiogenesis
   - HIF⍺ is a transcription factor for hypoxia genes
   - VHL is a tumor suppressor E3 ligase for HIF⍺
6. tissue invasion and metastasis:
   - adhesion and invasion of basement membrane
   - passage through ECM
   - invasion of vascular BM and vascular ingress (intravasion)
   - travel via the vasculature
   - adhesion to BM at destination
   - invasion of vascular BM and vascular exit (extravasation)
   - metastatic deposit
   - angiogenesis and growth

Question 8

Explain the steps in multistep carcinogenesis.

Answer 8

1. initiation:
   - exposure of cells to appropriate doses of a carcinogenic agent
   - irreversible changes in the genome
   - the amount of total exposure matters
2. promotion:
   - unregulated and accelerated growth of the mutated cells
   - triggered by growth factors and chemicals
   - may occur after long latency periods
3. progression:
   - acquisition of malignant characteristics (invasiveness, metastatic competence)

Question 9

List the systemic manifestations of cancers.

Answer 9

wasting syndrome:
- cancer anorexia-cachexia syndrome
- reduced food intake (anorexia) and wasting body fat and muscle tissue (cachexia)
- oral or parenteral nutritional supplementation does not reverse cachexia
- significant cause of morbidity and mortality

fatigue and sleep disorders:
- tiredness, weakness, and lack of energy not relieved by rest or sleep
- poor sleep quality, insufficient sleep, nighttime awakening, and restless sleep

anemia:
- blood loss, hemolysis, impaired RBC production
- drugs used in the treatment may also decrease RBC production

pain:
- common in late-stage cancers
- the most dreaded aspects of cancer
- pain management is necessary even for patients with incurable cancers

Question 10

Identify examples of targeted cancer therapy and cancer biomarkers.

Answer 10

methods of diagnosis:
- fluorescence in situ hybridization (FISH) to estimate the gene copy number
- immunohistochemistry (IHC) to assess protein expression and tissue distribution
- DNA sequencing

targeted cancer therapy:
- BCR-ABL translocation (BCR-ABL inhibitors, imanitib/Gleevec)
- estrogen receptor (ER) expression in breast cancer (anti-hormone therapy)
- HER2 over-expression (anti-HER2 antibodies, trastuzumab/Herceptin)
- EGFR mutations (EGFR inhibitors)
- Ras mutations (targeted inhibitors)

cancer biomarkers:

proteins that are highly expressed in cancer tissues can also be used as biomarkers in blood
- PSA (prostate specific antigen, prostate cancer)
- AFP (⍺-fetoprotein, primary liver cancer and germ cell cancer of the testes)
- CA 125 (cancer antigen 125, ovarian cancer)

not so useful for diagnosis due to the high false positive rates
- levels can be elevated by causes other than cancer
- can be used in combination with other diagnostic approaches

useful in monitoring treatment response and recurrence
- decrease after surgery or treatments confirms the effectiveness
- increase later may suggest tumor recurrence