Download Lecture 10

Biology 207
Biology of Cancer
Spring 2004
Lecture 10
"Cell Growth"
Readings: King, Chap. 10
Lecture Outline:
1. Cell Cycle
2. Cancer as error in controlling cell cycle
3. Growth of normal cells vs. cancer cells
4. Cell death pathways
Cancer definition: Cells growing "out of control".
What are the normal constraints on cell growth?
Some cells divide continuously
 hematopoietic (blood-forming) cells
 intestinal epithelia
 skin cells
Some cells divide often
 Epithelia of various types
 Some connective tissue cells
Some cells never divide in adults
 Nerve cells
 Cardiac muscle

These tissues not subject to cancer in adults, but childhood cancers
possible, such as neuroblastoma.
1. Cell Cycle
What happens when cells divide?
Interphase: Preparation for next cell division.
Distinct phases:
G1
Gap 1
S
G2
Synthesis phase
Gap 2
1
can vary for different cells,
cell growth occurs
DNA replication occurs
cell growth occurs
Mitosis:
Cell division of somatic (body) cells. Replicated
chromosomes are equally distributed among two daughter cells.
Length of Gap1 is highly variable.
 Slowly dividing cells exit G1 into G0.
 They wait for a signal to promote re-entry into the cell cycle.
Checkpoints: Before proceeding around the cell cycle, the cell checks its state.
G1/G0 checkpoint
 Assess whether nutrients and growth factors are available for growth
 Rb (retinoblastoma) protein and its metabolic state is involved in decision
o Acts like a molecular switch to decide whether the cell proceeds
through the cell cycle.
o If Rb has a phosphate group added to it, the cell cycle can move
forward.
o If Rb has the phosphate group removed, the cell stalls in G 0 of the cell
cycle.
G2/M checkpoint
 Is all DNA replicated?
 Is environment good?
 Are conditions in the cell favorable?
 p53 plays a critical role in checking for DNA damage
Mitotic metaphase checkpoint
 Are chromosomes correctly aligned in center of the cell for cell division?
Cancer as a defect in cell cycle control:


Many tumor suppressor genes and oncogenes encode proteins important
for controlling the cell cycle.
Some examples:
Component
PDGF (platelet derived
growth factor, encoded by
oncogene c-sis)
Rb (retinoblastoma, tumor
suppressor protein)
p53 (tumor suppressor
protein)
Role in cell cycle
Regulates cell growth
Cyclin D (cyclins are
unstable proteins involved
Helps cell proceed
through cell cycle
Needed for quiescence
Surveys for DNA damage,
triggers cell death if
needed
2
Defect in cancer
Signal cell to reenter
cell cycle when cell
should be quiescent
Cell can proceed
through cell cycle
Allows cell division to
proceed, often leading
to abnormal
chromosomes
Unregulated cell
growth
in the cell cycle)
Growth of cells in culture as model for cancer.
In vitro: " In glass". Experiments on cells conducted outside the whole
organism.
Primary cultures:
Animal tissue  culture dish + growth media + hormones + growth factors
Most cells grow for several generations, then eventually die:
Secondary cultures:
Primary culture  many passages, cells that grow are said to be immortalized
Some cultures more cancer-like, others more normal.
"Normal cells"
After several cell divisions, cells
become quiescent
Require growth factors to grow
Require surface to grow
Die after 50-100 divisions
Chromosome # mostly stable
Tumor cells
Cells continue to divide
Reduced need for growth factors
Become anchorage independent
Cells become immortalized
Chromosome # may vary--unstable
Other differences between normal cells and cancer cells observed in
animal studies of cancer (in vivo):
Observation*
Protease secretion
Secretion of angiogenic
factors
Can terminally
differentiate
Able to undergo
programmed cell death
Normal cells
Low
Low
Cancer cells (in vivo)
High
High
Able
Unable
Able
Unable
*Key terms:

Protease secretion refers to the release of protein digesting enzymes by
cancer cells.

Angiogenesis refers to the growth of blood vessels. Cancer cells stimulate
the growth of blood vessels to help obtain nutrients for the tumor.
3

Terminal differentiation refers to the ability of cells to mature into
specialized forms. Specialized cells usually do not divide. Cancer cells
lose the ability to terminally differentiate.

Most normal cells provide cues to the body that they belong; when things
go wrong, a cell death pathway is initiated. The body often loses the
ability to recognize cancer cells as abnormal and they escape the cell
death pathway.
4. Cell death pathways
Apoptosis=Programmed cell death--Precise sequence of intracellular events
that kill a cell when it is no longer needed by the body or it has been found to
contain a foreign (non-self) antigen.

A distinct category of oncogenes relate to the cell death pathway.
Example:

bcl-2 (associated with leukemias and lymphomas)
Under normal conditions, bcl-2 encodes a mitochondrial protein that
promotes cell survival.
In cancer, altered bcl-2 or too much bcl-2 results in not enough cell death.
Leads to proliferation of cells.
Lack of cell death is an important mechanism of cancer promotion among
cells of the immune system.


Pathways promoting apoptosis (Fig. 10.12)
DNA damage
↓
withdraw growth factors
(EGF)
↓
p53
death promoting signals
(TNF)
↓
caspase
cell death signals
(bcl-2 family proteins)
↓
cytochrome c release
from mitochondria
↓
activate caspases
↓
activate endonucleases
destroy nuclear matrix
proteins
4
destroy cytoskeleton