Ch 20: cancer Flashcards
Distinguish between different types of tumors and determine their tissue of origin
Carcinoma – from epithelial cells – most common
Myeloma, leukemia, lymphoma– from WBC and their precursors (hematopoietic cells)
Sarcoma – from connective tissue or muscle cells
Describe the hallmarks of cancer
- Altered homeostasis that results in cells growing and dividing at a faster rate than they die
- Bypass of normal limits to cell proliferation
- Evasion of cell-death signals
- Altered cellular metabolism
- Manipulation of the tissue environment for cell survival and to evade immune response
- Escape of cells from their home tissues and proliferation in foreign sites (metastasis)
Evidence for sequential accumulation of mutations
cataclysmic genome disruptions make genomes unstable, which makes it easier to accumulate mutations
aneuploidy
chromothripsis
Difference between oncogenes and tumor-suppressor genes
Oncogene - gene that through the gain of function can promote cancer; generally dominant
Tumor-supressor gene- loss of function can promote cancer; generally recessive
Mutations that lead to proto-oncogenes
Point mutation coding sequence–> hyperactive protein
Point mutation in regulatory site –> protein overproduction
Gene amplification –> protein overproduction
Chromosome rearragnement –> protein overproduction, hyperactive fusion proteins
Difference between stem-cell and differentiated cell tumors
Stem – self-renewing cells present in many tissues. When stem cells divide, they can either become a terminally differentiated cell or remain a stem cell
Cancer stem – self-renewing cells found within tumors that can give rise to fresh tumors when implanted in different tissue/ organ
Why do tumor cells have increased telomerase activity?
- can reactivate telomerase or evade death signals (ex p53)
- repair mechanisms
What is genome instability?
an abnormally high rate of genetic changes occurring within a cell’s genome
Examples of proto-oncogenes and tumor-suppressor genes
proto-onco: Myc, EGF receptor, src kinase
Supressor: , p53, Rb, Apc, Brca1, Brca2
What mutations innactivate a tumor suppressor gene?
genetic silencing –> chromosome abnormalities, point mutations, deletions
epigenetic silencing –> methylation of the promoter irreversibly silencing the gene
Why do colon polyps not necessarily become tumors?
Polyps develop from loss of Apc
Activation of K-ras, loss of Smad4, and loss of p53 are needed to become a tumor
What is EMT and how does it contribute to cancer?
when epithelial cells lose their polarity and adhesiveness to take on mesenchymal phenotype and migratory behavior
Cancer treatment approaches and their different efficacies
Generalized approach
Ionizing radiation and cytotoxic drugs: weakly selective, have detrimental side effects, can lead to secondary cancers
Targeted approach:
exploiting tumor’s genetic instability, target specific mutations to selectively kill cancer cells
What do PARP inhibitors do?
kill cancer cells that have mutations in Brca1 and Brca2
What does Gleevec (imatinib) do?
Inhibits oncogene Bcr-Abl, ultimately preventing leukemia
How does injecting antibodies treat cancer?
- inhibit function of cancer cell proteins
- trastuzumab inhibits Her2
Her2 overexpresses breast cancers
How can T cells be used as cancer treatment?
- CAR T therapy- collect patient’s T cells, engineer cancer-reactive population and reinfuse cells back to patient (augmenting T cell response to mutated cancer cells with neoantignets, which can be recognized as foreign)
- promoting T cell or dendritic cell infiltration into the tumor
How can developing immune checkpoint inhibitors promote remission?
prevent tumors from binding inhibtory T-cell receptors (antibodies for PD1 or PDL1)
Promotes T cell or dendritic cell infiltration into the tumor
Examples of how cancer cells can evolve to become resistant to therapies
resistance to PARP inhibitors due to reactivation of Brca gene
small group of cancer stem cells remains and continutes to proliferate
multidrug resistance
upregulation of gene Mdr1 or Abcb1-ABC transporters that pump lipophilic drugs out of the cells to prevent intracellular accumulation of cytotoxic anti-cancer drugs
What is a neoplasm?
- tumor
- a swelling of a part of the body, without inflammation, caused by an abnormal growth of tissue.
- A new and abnormal growth of tissue in some part of the
body
What 2 properties define cancer cells?
- Reproduction beyond the normal restraints on cell growth and division
- Invasion and colonization of territories normally reserved
for other cells
Primary tumor
- the original cell in tissue that gave rise to the tumor
- Can be traced back even after metastasis
- arises in a specific organ
which mutations can be passed down to progeny?
Germline
NOT somatic
Aneuploidy
gain or loss of individual chromosomes (uneven split) during
mitosis as result of both sister
chromatid attachment to the same pole
Chromothripsis
DNA damage and chromosomal rearrangement resulting from isolation of chromosome in a micronucleus
contact inhibition
when a cell touches nother cell, stops dividing. But cancer cells lose ability to respond to these signals and ignore them and continue dividing
Warburg effect
abnormally high glucose uptake that allows tumors to be imaged in whole-body scans
How do cancer cells gain energy?
glycolysis, not oxidative phosphorylation (so removing oxygen is not enough because not required for glycolysis)
Stroma
- connective tissue that surround the tumor containing fibroblasts, inflammatory white blood cells, blood vessel cells
- they are not cancer cells
- Cancer cells induce modifications of the ECM, modifying immune response and promoting angiogenesis
Metastasis
formation of secondary tumors invading other sites of the body
Steps:
1. Break free from the primary tumor
2. Enter the circulatory system
3. Exit the circulatory system at another
location
4. Form colonies of cells in the distant organ
Rb
Ras
p53
Rb: cell-cycle entry
Ras: signaling cascade that drives growth
p53: tolerance to stress and DNA damage
