Biology of Tumor Growth Flashcards
list the 4 phases of tumor growth
- transformation
- from a normal cell to a malignant cell (carcinogenesis)
- growth of transformed cell, angiogenesis, progression and heterogeneity
- local invasion
- distant metastases
most human tumors are derived from a ____ (aka ____ origin)
explain this
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
describe tumor cells’ resistance to apoptosis
- 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)
describe the limitless replicative potential (immortality) of tumor cells
- 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
describe metabolism by cancer cells
- Warburg metabolism: favoring glycolysis over oxidative phosphorylation is common in malignant cells
- many oncoproteins (RAS, MYC, mutated growth factor receptors) induce Warburg metabolism
describe autophagy of cancer cells
- 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
describe oncometabolites
- 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)
describe inflammation/stroma as an enabler of malignancy
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
describe genomic instability as an enabler of malignancy
inherited mutations of genes involved in DNA repair; increased risk for the development of cancer
give examples of inherited mutations of genes involved in DNA repair
- 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
describe angiogenic factors
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)
describe growth fraction (tumor growth)
- 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
describe the size of a clinically detectable tumor
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)
describe tumor cells’ invasion of extracellular matrix
- 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)
describe vascular dissemination and homing
- 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
describe tumor antigens
tumors with a higher number of ____ (___ and ___ cells) have a better prognosis
tumors with a higher number of infiltrating lymphocytes (CTL and TH1 cells) have a better prognosis
describe the grading of tumors
- 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
describe staging of tumors
- 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)
staging is based on TMN; explain this
- size of the primary tumor (T)
- extent of spread to regional lymph nodes (N)
- presence or absence of metastases (M)
tumor cells may escape the immune system surveillance by… (3 mechanisms)
- antigenic modulation
- outgrowth of antigen-negative clones
- increased production of proteins inhibiting CTL
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
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
