Biology of Tumor Growth

Question 1

list the 4 phases of tumor growth

Answer 1

1. transformation
   
   • from a normal cell to a malignant cell (carcinogenesis)
2. growth of transformed cell, angiogenesis, progression and heterogeneity
3. local invasion
4. distant metastases

Question 2

most human tumors are derived from a ____ (aka ____ origin)

explain this

Answer 2

most human tumors are derived from a single transformed cell (aka monoclonal origin)

• monoclonality of neoplastic cells
  
  • the tumor cells are derived from a single cell
• can be established by examining G6PD isoforms
  
  • in neoplasia: only 1 isoform
  • in hyperplasia: >1 isoform

Question 3

describe tumor cells’ resistance to apoptosis

Answer 3

• evasion of apoptosis mostly intrinsic (mt) pathway
• commonly by loss of p53 function, TP53 mutations, or overexpression of the p53 inhibitor MDM2
• overexpression of anti-apoptotic members of BCL2 family (BCL2, BCL-XL, MCL1)

Question 4

describe the limitless replicative potential (immortality) of tumor cells

Answer 4

• normal mature cells lack expression of telomerase, telomeres shorten, causing limited cell division leading to senescence
• tumor cells reactivate telomerase, thus staving off mitotic catastrophe and achieving immortality

Question 5

describe metabolism by cancer cells

Answer 5

• Warburg metabolism: favoring glycolysis over oxidative phosphorylation is common in malignant cells
• many oncoproteins (RAS, MYC, mutated growth factor receptors) induce Warburg metabolism

Question 6

describe autophagy of cancer cells

Answer 6

• during nutrient deficiency cells can cannibalize their own organelles as carbon sources for energy production–the cells die if this fails
• cancer cells avoid autophagy and can sustain their growth on marginal conditions

Question 7

describe oncometabolites

Answer 7

• some oncoproteins (products of mutated oncogenes) causes formation of high levels of abnormal metabolite, which leads to epigenetic changes and oncogenic gene expression
  
  • e.g. mutated isocitrate dehydrogenase (IDH)

Question 8

describe inflammation/stroma as an enabler of malignancy

Answer 8

release of factors that promote proliferation by infiltrating leukocytes and activated stromal cells

• removal of growth suppressor - proteases
• enhanced resistance to cell death: factors from tumor-associated macrophages
• angiogenesis: factors from inflammatory cells (VEGF)
• invasion and metastasis:
  
  • proteases by remodeling the ECM
  • TGF-B promoting epithelial-mesenchymal transition (EMT)
• evasion of immune destruction

Question 9

describe genomic instability as an enabler of malignancy

Answer 9

inherited mutations of genes involved in DNA repair; increased risk for the development of cancer

Question 10

give examples of inherited mutations of genes involved in DNA repair

Answer 10

• HNPCC: patients’ genomes show microsatellite instability (MSI), characterized by changes in length of short tandem repeating sequences
• xeroderma pigmentosum: defect in the nucleotide excision repair pathway
  
  • increased risk for the development of skin induced by UV light
• Bloom syndrome/ataxia telangiectasia/Fanconi syndrome: hypersensitivity to DNA-damaging agents

Question 11

describe angiogenic factors

Answer 11

chemotactic and mitogenic for endothelial cells

• induce production of proteolytic enzyme
  
  • fibroblast growth factors (FGFs)
  • vascular endothelial growth factor (VEGF)
  • platelet derived growth factor (PDGF)
  • hypoxia-inducible factor 1 (HIF1a)

Question 12

describe growth fraction (tumor growth)

Answer 12

• growth fraction = (# of cycling cells) / (# of total cells)
• earlier majority of the cells are in the proliferative pool
• tumors with high growth fractions are susceptible to chemotherapy

Question 13

describe the size of a clinically detectable tumor

Answer 13

1 cm³ (1 gm)

= 10⁸ to 10⁹ cells

= 30 doublings from a single cells not including cell loss

10 doublings from this stage = tumor size of 1 kg (lethal)

Question 14

describe tumor cells’ invasion of extracellular matrix

Answer 14

• detachment of tumor cells
  
  • reduced cadherins (normally causes cell adhesion)
• extracellular matrix protein degradation by enzymes
  
  • collagenase, cathepsin B
• attachments to the extracellular matrix protein components
  
  • laminin receptors, integrins
  • new sites generated b MMP2, MMP9 –secreted by tumors
• movement through extracellular matrix proteins
  
  • autocrine motility factors, cleavage products (collage, IGF)

Question 15

describe vascular dissemination and homing

Answer 15

• tumor cells erode through the wall of the lymphatics or blood vessels
• spread as:
  
  • single cell
  • multiple cell emboli with platelets and WBC
• the homing (metastatic site) of tumor related to:
  
  • presence or absence of specific molecules
  • chemo-attractant (chemokines)
  • unfavorable environment (muscle)
• in the new (metastatic) site
  
  • they grow
  • stimulate angiogenesis

Question 16

describe tumor antigens

Answer 16

Question 17

tumors with a higher number of ____ (___ and ___ cells) have a better prognosis

Answer 17

tumors with a higher number of infiltrating lymphocytes (CTL and TH1 cells) have a better prognosis

Question 18

describe the grading of tumors

Answer 18

• grade is the level of differentiation
• the method of grading is specific to the particular tumor
• commonly described as well, moderately or poorly differentiated tumors
• based on differentiation, mitosis and necrosis

Question 19

describe staging of tumors

Answer 19

• stage is the extent of spread and is usually more important that grade
• clinical staging is based on evidence acquired prior to the decision as to definitive treatment
• pathological staging includes information obtained at surgery and from examination of tissues by the pathologists (more accurate)

Question 20

staging is based on TMN; explain this

Answer 20

• size of the primary tumor (T)
• extent of spread to regional lymph nodes (N)
• presence or absence of metastases (M)

Question 21

tumor cells may escape the immune system surveillance by… (3 mechanisms)

Answer 21

1. antigenic modulation
2. outgrowth of antigen-negative clones
3. increased production of proteins inhibiting CTL

Question 22

blockade of the ____ surface molecule with an inhibitor antibody allows cytolytic CD8+ T cells (CTL) to engage _____ family coreceptors, leading to activation

blockade of ____ receptor or ____ ligand by inhibitory antibodies downregulates inhibitory signals transmitted by ____, leading to activation of CTLs

Answer 22

blockade of the CTLA4 surface molecule with an inhibitor antibody allows cytolytic CD8+ T cells (CTL) to engage B7 family coreceptors, leading to activation

blockade of PD1 receptor or PD1 ligand by inhibitory antibodies downregulates inhibitory signals transmitted by PD1, leading to activation of CTLs