Cancer Flashcards
What is a tumor?
A space occupying lesion that may or may not be a neoplasm
What is a neoplasm?
An abnormal growth with abnormal gene regulation
Two types: benign and malignant
What is cancer?
A malignant neoplasm
What is metastasis?
Secondary growth of cancer at different locations from the primary neoplasm
What are the three steps of carcinogenesis?
Initiation: mutation in one or more genes that control regulatory pathways of the cell
Promotion: involves gene activation or repression causing enhancement
Progression: continuing change of the unstable karyotype
What causes the initiation of carcinogenesis?
Genotoxic agents such as chemicals, ROS, radiation and viruses
At what stage of carcinogenesis can result in the conversion of benign tumors into malignant neoplasms capable of invading adjacent tissues and metastasizing to distant sites?
Progression stage
Cancer is largely the result of what?
Acquired genetic and epigenetic changes
What are some hallmarks of cancer?
Acquire self sufficient growth signals, become insensitive to growth inhibitor signals, evade cell death, limitless replication, angiogenesis, invade tissues and metastasize, create genome instability, promote inflammation, avoid immune destruction and reprogram energy metabolism
What are oncogenes?
Genes that stimulate cell division and growth (positive regulators)
Loss of regulation of expression can lead to enhanced expression of these proteins leading to uncontrolled cell division and growth
Activated by mutations or overexpression in carcinogenesis
Dominant (only one allele required)- gain of function
Ex. Ras and Myc
What are the three forms of oncogenes?
Cellular proto-oncogenes that have been captured by retroviruses
Cellular proto-oncogenes that have been mutated
Virus specific genes that behave like cellular proto-oncogenes
Which mechanisms can activate proto-oncogenes into oncogenes?
Truncation, point mutation, insertion and
gene amplification
What are tumor suppressor genes?
Genes that serve to check or inhibit cell division
Loss of expression of these proteins leads to cell growth or division
Recessive - loss of function
In carcinogenesis: inactivating mutations, deletions or loss of expression
Ex. Rab, p52, p14ARF, p16INK4A
What is the function of p53?
Tumor suppressor gene
Once DNA damage has been detected it can initiate programmed cell death if the damage cannot be repaired
Or if the damage can be repaired it activates the Cdk inhibitor p21 which stops the cell cycle
What is the second most commonly inactivated gene?
p16INK4A which has been shown to occur as an inactivation on chromosome 9 in human cancers
What is the tumor microenvironment (TME)?
Environment in which cancer cells exist that includes normal cells, secretory factors and extracellular matrix
What are the cellular components of the TME?
Immune cells, fibroblasts, other stroma cells, blood vessel cells and epithelial mesenchymal transition (EMT) cells
Which secretory factors are present in the TME?
Signaling molecules, growth factors, inflammatory factors and enzymes (MMPs)
What is in the extracellular matrix of the TME and what is its role?
Fibrous proteins and proteoglycans
Provide structural support for multicellular environment
On the molecular level, breast cancer is a heterogenous disease with molecular features including what?
Activation of epidermal growth factor receptor 2 (HER2 encoded by ERBB2)
Activation of hormone receptors (estrogen receptors and progesterone receptor)
BRCA mutations
Describe the estrogen receptor signal pathway for breast cancer
- Estrogen binds to ER-alpha (highly expressed) and ER-beta (low) inside the cell
- Ligand binding causes formation of homo/heterodimers
- Dimers move to the nucleus and bind to ERE regions on target genes and recruit co-regulators to achieve transcriptional regulation
Describe the HER2 signaling pathway in breast cancer
- HER2 (molecular oncogene) binds to its RTK on the cell membrane
- RTK is phosphorylated which initiates downstream oncogenic signaling pathways such as P13K/AKT pathway and Ras/MAPK pathway
What is an early genetic event that may be responsible for pancreatic cancer?
K-Ras mutation followed by loss of functional p16, p53 and SMAD4
Radiation as a form of cancer therapy is most effective on cells which have what?
Reproductive activity, cells that have a long dividing future ahead, and cells with morphology and function that are fixed
What is the mode of action for radiation in terms of cancer tx?
It can cause direct breakage of DNA bonds or it can cause hydrolysis of water which produces powerful damaging free radicals
Which agents are frequently used for chemotherapy?
Alkylating agents, intercalating agents, antimetabolites, mitostatic agents and platinum derivatives
Describe alkylating agents in chemotherapy
They are capable of denaturing DNA
Mode of action: cross link DNA chains
Describe intercalating agents and their role in chemotherapy
Interact with DNA and are intercalated b/w two bases inducing a structural change
Cleaving agents capable of breaking DNA molecules
Describe antimetabolites and their role in chemotherapy
Can be structural analogies of purines and pyrimidines
Block the synthesis of corresponding bases or can inhibit enzymes
Describe mitostatic agents and their role in chemotherapy
Inhibit tubulin synthesis
Cell spindle poisons
What role do platinum derivatives play in chemotherapy?
Play a role in DNA binding (can cross link DNA similar to alkylating agents)
What are the two major examples of immunotherapy?
Adaptive T cell therapy and personalized recombinant cancer vaccines
Describe adaptive T cell immunotherapy
T cells from donor or pt are isolated and genetically modified to express CARs that can bypass MHC restriction and direct specific cytotoxicity to a target molecular on the surface of the malignant cell
Describe personalized recombinant cancer vaccines as a form of immunotherapy
Healthy tissue and tumor tissue from a cancer pt are submitted for DNA analysis to ID gene variants specific to the tumor (neoAgs)
Algorithms used to screen for neoAgs binding to MHC molecules
Multiplied predicted neoAgs are then made into vaccines and given to the pt together with adjuvants
