Cancer Principles Flashcards
Cancer characterized by
general breakdown in lines of communication btwn cancer cell and its environment -> mutations -> alter expression and fx of genes that normally regulate cell proliferation, differentiation, and survival
cancer gene mutations can be
inherited, arise spontaneously in normal cells, and acquired during the evolution of the tumor
most cancer mutations occur in
somatic cells
age related incidence of cancer
cancer arises bc multistep process bc accumulate mutations in several genes including proto-oncogenes and tumor suppressor genes long latency period generally exists btwn first mutation and acquiring all others -> most cancers having late onset
tumor progression
accumulation of phenotypic trait characteristic of malignant neoplasia
hyperplasia -> dysplasia -> tumor -> metastasis
importnat colon cancer genes/ pathways
APC, PI3K, p53, TGF-beta pathway, ras; for diff types of cancers can ID genes that mutate at various stages of the cancer
APC
required for cell differentiation (acts as tumor suppressor)
ras
GTP protein involved in proliferative signaling acts as oncogene
PI3K
lipid kinase, acts as oncogene
p53
tumor supressor
TGF-B pathway
acts as tumor suppressor
epigenetic changes
ex DNA methylation pattern; alter normal gene expression and promote tumorigenesis
driver genes
responsible for development and progression fo individual tumor types
- oncogenes
- tumor supressor genes
What fosters tumor evolution and development of drug restiances
- Intra-tumor heterogeneity
2. Interactions between the tumor and tumor microenvionrment
intra-tumor heterogeneity
tumors are genetically and phenotypically heterogenous consisting of multiple subpopulations of cells with distinct properties; tumors are subject to harsh environments and only subpopulations of cells harboring mutations and epigenetic modifications with selective advantage will survive and proliferate and expand and populate tumor so tumor microenviorment major determinant of intra-tumor heterogeneity as it changes tumor adapts
what causes intra-tumor heterogenity
individual cells of tumor accumulate modifications
Gradually:
- as result of mutagen exposure and DNA replication erros
- Rapidly as consequence of genomic instability
- epigenetic changes may contribute
- splicing variants
tumor microenvironment plays critical role in
- development, evolution, and survival of primary tumor
- ability of tumor cells to invade surrounding tissue and metastasize to distant sites
tumor microenvionrment consists of
multiple cell types, ECM components, nutrients, and waste products
Tumor and TME connnection
dependent upon signals originating from the other; tumor cells recruit inflammatory cells, activate resident fibroblasts, and secrete factors that block immune fx promoting antiongenesis; they alter microenvionrmne to factor tumor cell
CAFs
cancer associated fibroblasts; these with recruited inflamatory cells secrete growth factors, cytokines, and other factors that promote angiogenesis along with secreting proteases (degrade ECM - activating ECM-associated growth factors) and promote tumor cell migration
Cancer stem cells niche
CAFs secrete appropriate conditions (niche) for generation and maintenance cancer stem cells
different microenvioments
tumor cells adapt to primary tumor, surrounding tissue, circulation, metazoic site
cancer stem cells
aka tumor initiation cells similar ro normal stem cells
- can undergo asymmetric cell division -> new CSC and proliferating transit amplifying cell that can differentiate
- > contributes to intra-tumor heterogeneity
- Most cells in tumor are not highly tumorigenic the cancer stem cells are the small subset that are**
- these are more resistant to traditional therapies
CSC identification criteria
- expression of stem cell specific markers and signaling patheays
- ability small # of these cells to form new tumors when translpanted into recipient mice
- following CSCs as they divide via lineage tracing experiments
CSC specific properties
- long term self renewal
- increased proliferative potential
- capacity to differentiate
- telomerase expression
- multi drug resistance
- enhanced DNA replari
- ability to remain quiescent
these enable tumors to proliferate indefiencly, regrow following chemo and radiation treatments, and establish metastases as secondary sites
Warburg effect
tumor-associateed increase in rate of aerobic glycolysis
Cancer cell metabolism
- utilize enhanced rate of glycolysis to generate ATP and provide glycolytic intermediates used to synthesize nucleotides and amino acids and TCA cycle to produce precursors for fatty acid synthesis
- increase glucose uptake for glycolysis
- increase glutamine uptake for TCA cycle
Cancer cells and stress
- normal cells have defense mechanism for damaged or aberrant cells triggered by cell stress -> cells temporarily (quiescence) or permanenty (senescence) growth arrest or apoptose
- abnormally proliferating cells experience various types cellular stressed so they must acquire mutations in additional driver genes to bypass these defeneses
norma cellular stresses
- metabolic
- proteotoxic
- mitotic
- oxidative
- DNA damage stress
Abnormally proliferating cells stressful sitations
- hypoxia
- oncogene expression
- genomic instability
- telomere erosion
likelihood of developing cancer
based on environmental and heritable factors can be mutagenic or non-mutagenic agents
mutagenic environmental risk factors for cancer
-directly mutagenize DNA or are metabolized into mutagens
- Chemicals (cigaret smoke, formaledehyde, benzene ect.)
- radiation (sunlight, radon Ect.)
viruses (FeLV ect.)
- antioxidants= chemicals that inhibit mutagenesis and decrease cancer risk
conversion of normal cell to pre-neoplastic cell
2 step process initiation and promotion
initiation
exposure to a mutagen (initiation) -> permanent change in DNA; usually activating mutation in gene that = pt of proliferation signaling pathway; direct carcinogens act as initiatiors
- irreversible
promotion
initiated cells are stimulated to proliferate (hyperplasia) (eg by growth factors); classified as indirect or co-carcinogens
- dependent on presence of promoting agent so reversible
how do initiation and promotion -> carcinogenesis
promotor -> initiated cells proliferating -> clonal expression of mutated cell ; proliferating cells at higher risk of aquiring mutations
driver gene mutations
can collaborate with original initiator mutation to produce a pre-neoplastic phenotype (dysplasia)
why are proliferating cells more likely to acquire mutations
- DNA réplication erros
- in proliferating cells mutations often copied during S phase before they can be repaired correctly -> mutations being fixed in genome and passed on to daughter cells
any factor that promotes proliferation (especially chronic proliferation_
increases risk of acquiring cancer promoting mutations and developing cancer
ex. chronic exposure to toxic chemicals -> damaged cells -> stimulate stem cell proliferation to replace lost cells
2. chronic inflamation
chronic inflammation
mutagenizes cells and stimulates proliferation increasing cancer risk; during inflammation response neutrophils and macrophages secrete growth factors and cytokines and produce ROS and reactive nitrogen species which can mutagenize DNA
hepatosarcoma
cirrhosis of the liver and hepatitis C virus both increase risk factors for this cancer; proliferating hepatocytes faced with chromic inflammation accumulate mutations over time that promote tumor development and progression
Heritable factors
inhertiting inactivating mutation in tumor spuressor gene or germline variant in specific genes such as carcinogen activating enzymes or carcinogen detoxifying enzymes or DNA repair protein variants can affect cancer risk
inactivating mutation in tumor supressor
increases individuals risk of developing cancer and developing it at earlier age than general pop
ex. BCRA 1 and 2 (breast cancer) and APC (colon cancer)
carcinogen activating enzymes
ex cytochrome p450 enzymes
decrease in these decreases cancer risk increase increases it
carcinogen detoxifying enzymes
ex superoxide dismutase, glutathione S-transferase
more = better less= higher risk cancer
DNA repair proteins
if decreased activity can -> increased cancer risk
Hallmarks of cancer
essential alterations in cell physiology shared by many cancer in vivo plus properties acquired via conversion fo porto-oncogenes to oncogenes and the inactivation of tumor suppressor genes
Original 6 hallmarks of cancer (essential alterations in cell physiology)
- sustaining proliferative signlaing
- evading growth suppressors
- resisting cell death
- inducing angiogenesis
- Activating invasion and metastasis
- Enabling replicative immortality
4 additional hallmarks of cancer (conversion protocol-oncogenes
-> oncogenes and inactivation tumor spuressor genes -> these)
- Deregulating cellular energetics
- Avoiding immune destruction
- Genome instability and mutation
- Tumor-promoting inflammation
is expression of single oncogene sufficient to transform primary cells
no; cells with single oncogene introduced to them will permanently growth arrest or undergo apoptosis have to have additional mutations to evade defenses to get oncogene
dysplasia
preneoplasic
