slide set 21 Flashcards
cancer cells are defined by:
reproduce without, or in defiance of, normal signals
invade and colonize areas reserved for other cells
non-cancerous somatic cells facts
- cells need signals to survive
- cells need signals to grow and divide
- cells need to adhere to a surface or other cells (or other proteins)
- damaged cells will activate apoptosis
cancer cells ignore all this!
how does a tumor begin
with one cell
microevolution
carcinomas
cancer of epithelial cells
80% of cancers are epithelial in origin
this is because epithelial cells are more exposed to elements (more on the surface)
sarcomas
connective or muscle cancer
leukemias and lymphomas
blood cell cancers
benign tumor
“oma” ex: adenoma
malignant
for epithelial, “carcinoma” EX: adenocarcinoma
for connective/muscle, “sarcoma” EX: chondrosarcoma
also over-profileration, but some cells escape basal lamina and can move beyond the cell
tumor cell population
cancer starts with a single cell
- but that cell reproduces and mutates as time passes
- mutations within the growing population:
- select for the fastest growing and least inclined to respond to signals
clonal origin
cancer starts with a single cell
evidence for clonal origin
- chronic myelogenous leukemia
- begins with rare event that leads to forming of Philadelphia chromosome
- all patients have a chromosome translocation between chromosomes 9 and 22 in all of the tumor cells
- creates a novel enzyme
- all patients with this type of cancer: every cell has the philadelphia chromosome
because cancer arises from a single cell, changes must be heritable (2 explanations)
- Must be mutation to genes
- somatic mutations because they occur in somatic cells (cells of the body) not germ cells (cells that will form eggs or sperm)
- Epigenetic changes
- heritable changes in gene expression from chromatin structure
- heritable = passed down to daughter cells, not offspring
- heritable changes in gene expression from chromatin structure
evidence that multiple mutations are required to turn a cell cancerous
- cancer incidence rises with age
- if a single mutation was sufficient and equally likely at any time, we would expect a linear rate of incidence
- instead, cancer requires multiple mutations before all normal regulatory controls are lost
2 big summarizing features
- cancer develops from a single cell
- multiple mutations are required to transform a cell
these were confirmed by sequencing entire genomes of single cells within a tumor
clonal evolution
- accumulation of mutations over time: slow at first
- tumor progression is an evolutionary process as new mutations increase cell proliferation
- there are sub-clones within tumors
- genetic diversity within a tumor
cancer cells are genetically unstable
- sequence mutations, chromosomes translocations, deletions, duplications, structure (heterochromatin)
- mitotic chromosomes:
- each chromosome should ONLY have one color
- color marks the sequence typicaly of that chromosomes in a normal cell
- each chromosome should ONLY have one color
hallmark 1 of cancer
cancer cells display altered control of cell growth
most normal cells stop proliferating once they have carpeted the dish with a single layer of cells
proliferation is inhibited by contacts with other cells: contact inhibition
cancer cells disregard restraints and continue to grow and pile on one another
hallmark 2 of cancer
cancer cells have altered sugar metabolism
A) cells that are not proliferating will normally oxidize nearly all of the glucose they import from blood to produce ATP through oxidative phosphorylation
cells only derive most energy from glycolysis when deprived of oxygen
B) Tumor cells produce abundant lactate even in presence of oxygen
bc of increased rate of glycolysis that is fed by a large increase in rate of glucose import
tumor cells resemble rapidly proliferating cells in embryos (and during tissue repair)
tumor growth involves both:
increased cell division and decreased apoptosis contribute to growth
cells still die within a tumor, just less death by apoptosis
hallmark 3 of cancer
avoid replicative senescence
- our somatic cells have limited capacity to replicated
- 25-50 times for human fibroblasts
- The length of the telomere at the ends of chromosomes shortens with each replication
- cancer cells can re-express telomerase, which extends telomeres and prevents replicative senescence
tumor cells in context
the microenvironment and local signals contribute to tumor growth and speed
communication among different cell types play a role in tumor development
Recall: most cancers are of epithelial origin
cells must break cell-cell contacts and get through the basal lamina to spread
metastasis
a multi-step process that few cells can survive
mutations include:
- change in chromosome copy number, intra and interchromosomal rearrangements
- also point mutations
- sequencing all protein coding regions:
- ~50 genes are mutated in several cancers
mutations
some mutations drive cancer progression. Others are passengers.
- current best guess: ~300 genes are critial for cancer development and progression
- need >1 driver mutation, maybe up to 10
driver mutations are common throughout biology
Driver mutations:
two broad types of cancer-critical mutations
oncogenes: gain of function mutations lead to cancer
tumor suppressor genes: loss of function mutations (recessive, both alleles of cancer-critical gene must be lost)
~300 mutated proteins fall into a few key circuits and signal transduction pathways
EXAMPLE: Glioblastoma
- 91 patient tumors were sequenced
- Mutations in 3 pathways stood out as commonly hit (~75%)
- Broadly, these control:
- cell growth
- cell division
- responses to stress and DNA damage
