Introduction to Cancer

Question 1

1. Tumour
2. Cancer

Answer 1

1. Any tissues mass, solid - or liquid -filled, benign or malignant
2. Cancer - Malignant tumours, which have the potentual to metastasize
   
   • Neoplasia - a type of growth that continues despite the absence of stimulus

Question 2

Differentiation

Answer 2

• The morphology of the cells compared to normal cells of the same tissue.
  
  • Well-differentiated tumour - cells look and function like normal cells of the tissue
  • Poorly differentiated tumour (anaplastic) - cells do not function like normal tissue and appear abnormal
    
    • Pleomorphic - continual variation in sze and shape
    • Hyperchromatc - cells are dark staining with large nuclei
    • Loss of polarity - normal cells are anchored and oriented to basement membrane; anaplastic cell lack this and lose uniform oritentation
    • Mitosis - increased proliferation results in anormally large number of cells undergoing mitosis

Question 3

Grading Cancer

Answer 3

• Referes to the degree of differentiation in the tumour cells
  
  • high grade indicates poorly differentiated and more aggressive than low-grade

Question 4

Cancer Staging

Answer 4

• Refers to the size of the primary tumour and extent of local and distant spread
• T = tumour size and local invasion (T₀ - T₄)
• N = regional lymph node involvment (N₀ - N3​)
• M = distant metastases (M₀ - M1​)

Question 5

Cell cycle regulation

Answer 5

• M phase - cell undergoes mitosis and divide
• G₁ phase - First gap phase. Can be divided into early and late state, serparated by the restriction (R) point. Cyclin and cylcin dependent kinases (CDKs) control progression by phosphorylation of regulatory proteins.
  
  • The early phase in mitogen -dependent and requries the presence of growth factors for progession beyond this point. The late phase does not require mitogenes.
• G₀ phase - cells can exit the cell cycle to the G₀ phase if no mitogens are present
• R point - “point of no return” where the cell is committed to progression to the next phase - hyperphosphorylation of RB by CDK4/cyclin D is important in passing through the R point.
• G₁/S checkpoint - controlled by CDK₂ - checkpoint requries no damage to the DNA structure before DNA replication proceeds.
• S phase - DNA replication
• G₂ phase - second gap phase allows replicated DNA to be checked before mitosis

Question 6

Growth factors/ mitogens

Answer 6

• Soluble factors related by cells to infulence the gorwth of neighbouring cells or itself (paracrine and autocrine signalling respectively)
• Neoplastic cells can alter growth factors signalling to increase proliferation. Ex:
  
  • Autocrine stimulation - tumour cells may screte growth factors to stimulate self-growth
  • Constitutive activation - the growth factor receptor is altered so that it remains active
  • Overexpression - tumour cells overexpress growth factor receptors, leadind to increased signalling

Question 7

Apoptosis and Cancer

Answer 7

• Accumulation of DNA damage in carinogenesis usually results in triggering of cell apoptosis. In order for neoplasia to occur, the cell must evade this. Ex:
  
  • BCL2 - anti-apoptotic protein, commonly upregulated in cancers to protect against apoptosis
  • p53 - pro-apoptotic protein, commonly downregulated in cancers to evade apoptosis

Question 8

Senescence and Cancer

Answer 8

• Usually, health cells can only divide a limited number of times before becoming senescent due to the reduction in telmere length. At a certain point, DNA repair mechanisms (i.e., p53 and pRB) detect the shortened length and induce cell cycle arrest.
  
  • An enzyme called telomerase allows lengthening of telomeres after each dividion, allowing the cell to evade senescence and continue replicating despite increased DNA damage (can occur in tumour cells).

Question 9

Cancer and Genetics

Answer 9

• In carcinogenesis, pre-malignant cells accumulate genetic mutations until a fully malignant phenotype forms
• Most cancers are due to sporadic mutations rather than inherited
• There are 2 main groups of genes implicated in cancer - onogenes and tumour suppressor genes. A malignant tumour often has activation of oncogenes and inactivation of tumour suppressor genes.

Question 10

Types of cancers onocogenes vs. tumour suppressor genes

Answer 10

• Most blood cancers and soft-tissue sacromas are initiated by activation of oncogenes
• Most carcinomas are initiated by loss of tumour suppressor genes
• Susequent progression of malignancy involves both additional gain of oncogenes and loss of tumour suppressors in all types of cancers

Question 11

Proto-oncogenes

Answer 11

• A group of genes that cause normal cells to become cancerous when they are mutated
  
  • Mutations in these genes tend to be dominant
  • Mutated proto-oncogenes = Oncogenes
• Proto-oncogenes encode proteins that function to stimulate cell division, inhibit cell differentiation, and halt cell death. Thus, oncogenes result in increased production of these proteins resulting in increased cell division, reduced cell differentation, and inhibition of cell death.
• Mutations in proto-oncogenes can be either quantitative (increasing amount of gene product) or qualitiative (ex. altering gene product to make it consistutively active)

Question 12

Tumour suppressor genes

Answer 12

• Endogenous genes that restrict cell proliferation by controlling cell division, repairing damaged DNA, inducing apoptosis when other mechanisms fail
  
  • Cancer cells harbour loss-of-function tumour suppressor mutations, resulting in no cell growth restriction. Loss of both alleles of tumour suppressor is required for cancer formation (2 hit hypothesis)
    
    • 2 hit hypothesis explains why children who inherit one mutated RB₁ allele are predisposed to retinoblastoma. Althoug children who have normal RB₁ alleles can also develop retinoblastoma (sporadic form), those whi inherit a mutation (hereditary form) have earlier onset of disease, increased risk of bilateral retinal involvement and mutlifocal rather than unifocal in origin.

Question 13

1. Categories of Tumour suppressor Genes

Answer 13

1. Gatekeeper genes - stop cell cycle progression when DNA damage is detected
2. Caretaker genes - repair damaged DNA during cell cycle arrest

Question 14

Carcinogenesis

Answer 14

• Carcinogenesis - multistep process of transformation of normal tissue cell to a cancer cell. Steps:
  
  • Initiation - A carcinogen induces non-lethal mutation in a cell. Cell undergoes one cycle of proliferation to make the mutation heritable.
  • Promotion - An initiated cell proliferates (clonal expansion), allowign additional mutations to accumulate
  • Progression - Continueal accumulation of multiple mutations results in an invasive phenotype and distant metastasis

Question 15

Classes of carcinogens

Answer 15

• Initiators - induces non-lethal mutation in cell, irreversbility chaning DNA. Must be exposed to tissue before promoter for carcinogenesis
• Promoter - induces cell proliferation (reversible influene on cell growth - i.e., no changes to DNA). Must be exposed to tissue after initiator for carcinogenesis

*Need exposure to both in order for carcingoenesis to occur (some carcinogens are both initiators and promoters)

Question 16

Retinoblastoma

Answer 16

• Retinoblastoma (Rb) - a rare form of cancer that rapidly develops from immature cells of the retina.
• Most common type of intraocular malginancy of childhoos and accounts for 10-15% of cancers within first year of life.
• Rb can be heritable or non-heritable:
  
  • Heritable Rb - associated with germline mutations in retinoblastoma (Rb1) gene. Includes patients with bilateral disease, multifocal disease, those with positive family history and those with germline mutation
  • Nonheritable Rb - results from somatic mutations in RB1 gene. Includes patients with unilateral, unifocal disease & tend to be diagnosed at alater age compared to heritable Rb.
• Accounts for ~13% of cancers in the first year of life. Median age of diagnosis is 18-20 months

Question 17

Pathogenesis

Answer 17

• Rb is caused by mutation inactivation of both alleles of the RB1 gene. RB1 encodes a nuclear protein (RB) that acts as a tumour suppressor. Rb proteins restricts the cells ability to progress from the G₁ phase to the S phase of the cell cycle. Loss of funcational RB results in cell cycle dysregulation.
  
  • 2 hit hypothesis
  • In heritable RB - germline mutation of RB1 or deletion is present in all body cells and then a second “hit” occurs later in development and affects the remaining RB1 allele. In nonheritable, both allic mutations arise spontaneously in a signal somatic cell of the retina.

Question 18

Progression of Retinoblastoma

Answer 18

• Deadly if untreated. Tumours grow and fill the eye and destroy the globe. Metastic spread is typically diagnosed with first 12 months of clinical presentation. With treatment the survival rate is >95%

Question 19

Answer 19

Question 20

Gastrointestinal Stromal Tumors (GIST)

Answer 20

• Stromal or mesenchymal neoplasms affecting the GI tract, most often located in the stomach and proximal small intestine.
  
  • Most common nonepithelial neoplasma involving the GI tract
• GIST is thought to be due to a gain of function mutation in the KIT gene (a proto-oncogene). In normal cells, KIT receptr kinase activity is regulted by binding of endogenous ligand for the receptor. KIT mutations lead to constitutive, ligand-independent activation of KIT, resulting in constitutive activation of downstream signaling pathway stimulate cell survival, growth, and proliferation

Question 21

Metastatic Cancer

Answer 21

• Metastatic Cancer is when the cancer has has spread. Cancer cells can spread locally by moving to nearby normal tissue, or regionally to nearby lymph nodes, tissue, or organs. In metastasis, cancer cells brek away from where they first form (primary cancer), travel through the blood or lymph system and form new tumours (metastatic tumour) in other parts of the body. The metastatic tumour is the same type of cancer as te primary tumour.
• When observed under microscope, metastatic cancer has features like that of the primary cancer and not like the cells in the place where the cancer is found.