senescence Replicative and loss of telomerase typically control the ability of non-stem cells to proceed through S-phase:
Stem cell populations (grey) are self-renewing, with one daughter retaining the ability to enter the cell cycle, while the other usually exits the cell cycle and differentiates (orange).
etc...
Tumor cells escape proliferative controls through accumulation of genetic changes (i.e., mutations!):
While determined and differentiated cells are supposed to stay in G0, sometimes outside factors lead to genetic changes in a cell that now frees it from its determined state, and allows it to re-enter the cell cycle. Note that in almost all cases, these cells keep at least part of their differentiated state! This is why we can usually identify the original cell/tissue source of tumors (i.e., leukemia, sarcoma, etc.) Fortunately, most cells that have accumulated sufficient mutations to escape proliferative controls are typically identified by immune surveillance, or become constrained by other cellular controls that would tend to trigger apoptosis (PCD); thus removing the threat. But, once a cell has accumulated some genetic changes, others tend to follow, including the ability to repress (or ignore) PCD signals, and to avoid immune response. This allows further unconstrained growth, resulting in a tumor. If such a tumor remains at the point of origin and does not accumulate further changes, we call such tumors benign.
etc...
Depending on the particular cell fate and other developmental signals, sometimes the other daughter is not determinate (green), and retains a limited ability to enter the cell cycle before becoming determined and differentiated. Such changes are dependant upon the local environment, a particular genetic program or developmental cues that lead to changes in cell behavior or gene expression without changes to the genome (mostly)... One mechanism of controlling the determination of a cell is a phenomena called replicative cell senescence which mainly involves the telomeres. Every time a cell goes through S-phase, the telomeres get shorter. Eventually, the telomeres are so short that they trigger a G1-checkpoint that blocks passage through S-phase. Stem cells express telomerase that restores their telomeres at every cycle. Determined cells express very little telomerase (or none at all), which puts an intrinsic limit on the number of times that cell can go through S-phase.
Once a cell has escaped proliferative controls and has failed to respond to proapoptotic signals, it tends to quickly accumulate other genetic changes:
A single mutation is not enough to cause cancer!
The cells of an established, aggressive, malignant tumor will have accumulated many mutations that were necessary to create the conditions that allow the cancerous cells to: 1) proliferate 2) avoid cell cycle checkpoints 3) avoid or ignore pro-apoptotic signals 4) acquire the additional nutrition to support growth 5) avoid immune surveillance 6) metastasize etc...
Typically, benign tumors remain small because they quickly become limited by food or oxygen. But, sometimes the body will respond to local anoxia by increased blood vessel growth into the area. Or, some tumors acquire new mutations that trigger production of endothelial growth factors by the tumor cells that enhance angiogenesis. Either way, the tumor now becomes well-fed and can continue to proliferate.
metastasis The "worst case" scenario occurs once some cells in such tumors pick up even more genetic changes that allow migration from their point of origin (i.e., "metastasis") or the tumor simply grows enough to allow invasion of adjacent tissues by breaking through a basal lamina. Such tumors are called malignant and are the typical things we call "cancer".
This is why cancer is usually a disease of later life, since the longer we live, the more mutations we accumulate in our somatic cells.
1
The Cell Cycle and Checkpoints represent the standard proliferative controls:
The G1 checkpoint is controlled by proteolysis of G1/S-cyclin and an S-cyclin inhibitor Most cells remain in G0 until signaled to enter the cycle by external cytokines. Even in the presence of cytokines, the cell first will make sure that the DNA is undamaged and that there are sufficient resources to proceed with cell division. If these conditions are met, the activity of the G1- and G1/S-cyclin/Cdk complexes help prepare the cell for DNA replication (and for exit from the resting G0 state). This checkpoint is eventually bypassed when an S-cyclin inhibitor and the G1/S-cyclins, are ubiquitinated by an E3-SCF complex and then degraded in the proteosome. The uninhibited S-cyclin/Cdk complex then accelerates the cell into S-phase.
Checkpoints are controlled by two classes of proteins: "brakes" and "accelerators"
1. The factors that block progression past a checkpoint ("brakes") are called Tumor Suppressors. If a cell picks up loss-of-function mutations in both copies of a tumor suppressor, progression past the checkpoint can't be stopped, even if conditions aren't "right", or if the cell is receiving "stop" signals! 2. The factors that trigger progression ("accelerators") are called Proto-Oncogenes. Normally, these don't work until the tumor suppressors signal that progression is OK, but if cells pick up gain-of-function mutations (i.e., "always on") in any copy of an proto-oncogene (turning it into an oncogene), then they will `accelerate' through the checkpoint regardless of any signals!
START
S
The G2 checkpoint is controlled by antagonistic protein kinases The cell will halt in G2 (sometimes resting here like G0) until the DNA is completely replicated, no DNA damage is identified, and the environment is favorable for progression. During G2, a pair of antagonistic kinases (Wee1 and CAK) keep the M-cyclin in an inactive state. The checkpoint is bypassed by allowing the activating kinase activity to become predominant.
Tumor Suppressors "brakes"
Proto-Oncogenes "accelerators"
G1 G2 M
-
+
A third class of factors involving responses to programmed cell death are also involved:
3. Inappropriate response to PCD signals can also lead to problems. Loss-of-function mutations in both copies of pro-apoptotic components (i.e., tumor suppressors) or gain-of-function mutations in anti-apoptotic factors (i.e., proto-oncogenes) would lead to a failure to undergo PCD.
START
The metaphase checkpoint is controlled by proteolysis of the M-phase cyclin: The cell will pause prior to anaphase and wait until the chromosomes all are attached to the spindle. Cells will only arrest here when things have gone horribly wrong! The checkpoint is bypassed when first the S-Cyclin/ Cdk and then the M-Cyclin/Cdk complex are ubiquitinated by the E3-APC and then degraded by the proteosome.
G1
S
"Braking" or "Accelerating" at a cell cycle checkpoint is the summation of signal transduction pathways. Mutations at any point in the signal transduction pathways can lead to failure to break or to undergo PCD (loss of a tumor suppressor) or to inappropriate acceleration (presence of an oncogene).
The checkpoint factors of the cell cycle represent the canonical proto-oncogenes and tumor suppressors:
For example, the G1 checkpoint:
1. The transcription factor E2F will bind to and trigger expression of S-phase genes if it is active. 2. E2F is kept inactive most of the time due to interaction with Rb 3. Rb can be inactivated though phosphorylation by the G1-cyclin/Cdk complex. 4. The G1-cyclin/Cdk complex is kept inactive by a Cdk-inhibitor p16 5. p16 is present is in stressed cells and serves as one measure of the status of the cell at "START"
Many cancer cells have mutations in both copies of Rb and p16 (tumor suppressors!), which results in promotion of the proliferative state.
2
Many components of signal transduction pathways act as proto-oncogenes or tumor suppressors:
Some tumors have gain-of-function mutations in Ras* which leads to a mutant form that is locked in the GTPbound state. This constitutively active form of Ras* (an oncogene!) signals even in the absence of cytokines or any other upstream part of the pathway!
Ras*GTP
In a broad sense, the factors involved in response to apoptotic signals also act as proto-oncogenes or tumor suppressors:
Under normal conditions, Bcl2 keeps the pro-apoptotic BH123 proteins from aggregating to form a pore in the mitochondrial OM. This anti-apoptotic activity of Bcl2 is insufficient to prevent aggregation when apoptotic stimuli are present, so factors like Cytochrome-c get into the cytosol and activate the apoptosome.
BH123 pro-apoptotic Bcl2 anti-apoptotic apoptotic stimulus
Under normal conditions, a receptor kinase activates upon binding a cytokine. The activated receptor kinase leads to activation of Ras, which then leads to a MAP-kinase cascade, eventually leading to a pathway that promotes passage into S-phase.
cytokine RasGDP RasGTP
Some tumors contain a mutation that leads to an overproduction of the anti-apoptotic protein Bcl2 (a Bcl2 oncogene). This excessive amount of Bcl2 prevents the pro-apoptotic BH123 proteins from aggregating, no matter how strong the apoptotic stimulus.
BH123 pro-apoptotic Bcl2 anti-apoptotic apoptotic stimulus
GDP
cyt-c not released
GTP
Cytochrome c pro-apoptotic
Cytochrome c pro-apoptotic
to cytosol
to nucleus
to cytosol
to nucleus
In this sense, anti-apoptotic proteins like Bcl2 act like proto-oncogenes and proapoptotic proteins like the BH123 proteins act like tumor suppressors.
This will not trigger proliferation of these cells, but it will keep those cells alive long enough to perhaps acquire other mutations that will trigger proliferation.
Fig. 15-58, 15-60
Blocking angiogenesis by tumors may eventually become an important anti-cancer treatment:
Because of the high nutritional demands of a fastgrowing tumor, getting a secure food supply is important to long-term success. "Successful" tumors tend to induce angiogenesis in nearby arteries, leading to formation of new arteries that can deliver food and oxygen directly to the growing tumor. The simple lack of O2 is a significant signal, but some tumors amplify this response by producing VEGF (vascular endothelial growth factor) which stimulates production of new arteries in the area. Aside from providing nutrients, the new arteries also provide a mechanism for eventual metastasis of some tumor cells, turning a benign tumor malignant. Some drugs that block angiogenesis work e...