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2.3.1 Cancer Biology Cheat Sheet (DRAFT) by

This is a draft cheat sheet. It is a work in progress and is not finished yet.

Cancerous growth and classi­fic­ation

Cancer cells are charac­terised by two distinct heritable proper­ties, which discri­minate them from normal cells.
First, they and their progeny reproduce despite the normal constr­aints that inhibit cell division and prolif­era­tion. Cancer cells prolif­erate more than the surrou­nding normal cells and so eventually crowd out and damage the local tissue.
A tumour or neoplasm is a relentless growing mass of abnormal cells.
Second, cancer cells invade and colonize territ­ories normally reserved for other cells.
The invasion of cancer cells into other cellular territ­ories is called “metas­tas­is” and it may be local or distant.
Third, cancel cells are geneti­cally unstable.
Fourth, cancer cells evade limita­tions to cell prolif­eration escaping replic­ative senesc­ence.
Fifth, cancer cells have lost the ability to differ­ent­iate.
Cancer may be classified into two types benign or mali­gnant
As long as the cancer cells remain clustered together in a single mass enclosed in a fibrous connective tissue or capsule the tumour is classified as benign and may be completely cured by surgical excision (assuming it is accessible surgic­ally).
A tumour is classified as mali­gna­nt, if its cells have the ability to invade the surrou­nding tissue. Such cells may break loose and enter the blood stream or invade draining lymph nodes. The more widely and rapidly a cancer spreads or metast­asises the more difficult it may be to treat.
Cancers are classified according to their tissue and cell type of origin.
Cancers arising from epithelial tissues are called “car­cin­omas”
Cancers arising from connective tissues or muscle are called “sar­com­as”
Cancers arising from hemato­poietic tissue are called “leu­kae­mia”
Cancers arising from lymphoid cells and tissues are called “lym­pho­mas”
Each cancer cell often demons­trates features that reflect the cell of origin, however, as cells become more and more malignant this may become increa­singly difficult for the pathol­ogist to discri­minate by microscopy alone.

Identi­fic­ation of Type of Cancer by Pathol­ogist

Pathol­ogists are able to identify the relative stages in cancer develo­pment from biopsy specimens that are obtained.
Hist­opa­tho­logy and spec­ialized stains enable the identi­fic­ation of normal cells, low-grade cancer lesions through to high-grade tumours, and in many cases the cell of origin can be identi­fied.
These various pathol­ogical classi­fic­ations for the most part reflect the cell of origin of the cancer, and are extremely important in predicting disease outcome and prognosis, likelihood and sites of metastasis and are essential for approp­riate treatments i.e. no treatment versus local treatment, versus chemot­herapy plus or minus radiot­herapy.
There are various sub-sets of the benign tumours including aden­omas, which is a benign epithelial tumour, which may undergo mali­gnant transf­orm­ation to become an aden­oca­rci­noma.
The surgeo­n/p­hys­ician will use the histop­ath­ology of a benign or malignant tumour to decide whether the lesion has been completely excised and if it is likely to further metast­asise.
The majority of human cancers are carcinomas of various different sub-ty­pes.
Each carcinoma may arise from a distinct cell type and follow an extremely different disease profile and outcome.
In low-grade lesions of epithelial tumours the cancer cell may clearly resemble the cell or origin, but may have started to prolif­erate and the dividing cells may escape the basal layer of the epithe­lium. In high-grade lesions, (that is moderate to severe cancer), the cells appear much more undiff­ere­ntiated and demons­trate a highly variable cell and nuclear size and shape.
Abnormal mitotic figures are frequently seen, evidence of genetic instab­ility of the tumour. The transf­orm­ation of the cell from a low-grade lesion to a high-grade lesion arises by successive cycles of DNA mutation and natural selection.
The acquis­ition of additional DNA mutations generates a selective advantage of the mutated cell over its normal neighb­ours, facili­tating increased prolif­era­tion, overcoming natural barriers to growth in the surrou­nding tissue.
Many successive rounds of genetic mutation are required, as cells contain many distinct regulatory systems, which inhibit abnormal cell prolif­era­tion. Tumour prolif­eration and expansion requires mainte­nance of its own oxygen and nutrients and the ability to overcome physical barriers at both the local site and at distant metastatic sites.
Pathol­ogists and scientists have developed special stains, antibodies to surface proteins and key components of the cytosk­eleton and signalling pathways, together with chromo­somal and DNA analysis to help to identify specific cancers and various subtypes.
This is important as the cancer type and the cell of origin dictates specific therapies.
The change from a normal cell to a cancer cell is called “cell transf­orm­ation”.
Cancer cells lack the structural features and cellular functions of normal cells. Cancer cells typically show an enlarged nuclei, dense DNA and changes to the cytosk­eleton, so that the cell is unable to maintain its normal shape.
Pathol­ogists have long recognized that there is spectrum of histol­ogical features that correlate with the progre­ssion of cancer. These include abnormal cellular morphology and presence of mitoses, or “mitotic index” and assessment the degree of invasi­veness of the tumour.
There is now strong evidence that these histol­ogical and clinical charac­ter­istics have a molecular basis. There is much data to suggest that cancer develops and becomes more malignant, as multiple genetic abnorm­alities accumulate in the cell.
By the time of clinical presen­tation most cancer cells will demons­trate evidence of genetic instab­ility. This will include the inability of the cancer cell to repair DNA damage, or correct replic­ation errors in specific nucleo­tides. Many cancer cells are unable to maintain the integrity of their genome.
This genetic instab­ility increases the likelihood that a cancer cell will experience a mutation in a gene such as a proto-­onc­ogene or a tumour suppressor gene, which plays an important role in either promoting or inhibiting cell prolif­era­tion.
These genes are critical genes that regulate cell growth and the cell cycle. As the tumour becomes increa­singly malignant, through the successive acquis­ition of mutations in the DNA, evidence of genetic instab­ility becomes more apparent. Chromo­somes can be seen to have abnorm­alities in structure and number, in prepar­ations of metaphase chromo­somes of tumour cells.
It is probable that cells, which maintain an optimum level of genetic instab­ility, may be the most likely tumour cells to survive
In normal cells, genetic instab­ility is rare. The presence of genetic instab­ility in tumour cells makes it increa­singly likely that at least one cell within the tumour cell acquires a mutation. This may allow the cancer cell to overcome certain selection barriers, which include the ability of the cell to prolif­erate under less than optimum condit­ions, such as under low oxygen condit­ions, or in the absence of specific growth factor stimul­ation.
However, if the level of genetic instab­ility becomes too high and serious mutations occur, this may lead to extinction of the abnormal cell. Thus for a cancer cell to survive it requires some level of genetic instab­ility, so that it has survival advantage, but does not acquire so many mutations that it becomes extinct.
Cells that are more rapidly cycling through the cell cycle are more likely to acquire DNA mutations and there is less time during S phase for repair.

Escaping Cell Senescence

Senesc­ence: loss of a cell's power of division and growth.
Normal highly differ­ent­iated cells do not divide. This ability to stop prolif­erating is called “Cell Senesc­enc­e”.
This may be a mechanism to prevent cancer develo­pment. Cell senescence in human cells is mediated by the shortening of telomeres, which are the repetitive DNA sequences and associated proteins that cap the end of each chromo­some.
The enzyme “Telom­erase” maintains these repetitive telomeric sequences. In adult human cells the gene encoding for the catalytic subunit telomerase is switched off, or not fully activated, therefore the telomeres in these cells tend to become a little shorter with each successive cell division, and eventually the telomeric cap on the chromosome can become danger­ously shortened, arresting the cell cycle preventing cell division, as long as the cell contains broken or inadequate DNA.
In normal cells that still produce functional p53 and have intact cell cycle checkp­oints, this shortening of the telomerase results in an arrest of cell division, i.e., “rep­lic­ative senesc­ence”
In cancer cells or pre-cancer cells, which have acquired mutations in p53 or specific cell cycle checkpoint proteins, the shortening of the telomerase and the signal generated maybe ignored, and the cell cycle progresses resulting in massive chromo­somal damage. The accumu­lated mutations may promote cancer develo­pment.

Normal cell growth and differ­ent­iation

The number of cells in a multic­ellular organism is usually tightly controlled with a balance existing between the rate of cell division and differ­ent­iation, and the rate of cell death.
In the fully developed human body, the total number of differ­ent­iated functional cells making up a particular tissue does not change signif­ica­ntly, with most tissue cell popula­tions being subject to slow turnover through cell division or differ­ent­iation, and cell death.
As cancer is caused by disruption of the control of cell growth and differ­ent­iation, it is important to understand the molecular mechanisms that regulate the normal cell cycle and control cell death.
Some cells persist throughout the lifetime of the organism without cell divisi­on. These include nerve cells, heart muscle cells, sensory receptor cells for light and sound, and lens fibres.
Cells of other tissues, lost through cell death or damage, are replaced either by mature cell division, or differ­ent­iation of stem cells.
The liver is an example of a tissue subject to slow turnover. Following liver damage, cells simply divide to produce daughter cells of the same type. In tissues such as the intestinal epithe­lium, the hemato­poietic system, or the skin, which have a very rapid turnover, damaged cells are rapidly replaced by adult stem cell differ­ent­iation.
Stem cells by definition are not terminally differ­ent­iated and have the ability to divide throughout the lifetime of an organism. Pools of stem cells yield some progeny that will differ­entiate into more specia­lized cells and others that remain stem cells with the capacity to self renew.
Terminal differ­ent­iation of these progenitor cells is stimulated by growth factors and cytokines resulting in cellular specia­liz­ation in terms of cell structure and function, specific for the tissue type. These highly differ­ent­iated cells that make up a functional tissue will, in general, retain their specific proper­ties, even when placed in a novel enviro­nment and will not interc­onvert to another cell type.
Failure in the regulation of cell division and differ­ent­iation or cell death results in serious effects on the tissue or organ function.
Cancer is a product of uncont­rolled prolif­eration of a single cell and often results from loss of control of cell division coupled with a lack of apop­tosis – (progr­ammed cell death)
Each phase of the cell cycle is tightly controlled and has a specific set of checkp­oints at which time the cell cycle can stop.
The major checkp­oints in a cell cycle are the checkpoint G1, just before entry into S-phase and the checkpoint at G2, just before entry into mitosis.
When enviro­nmental circum­stances forbid cell division, most cells will stop at G1, as this is the point if the cell does not stop it will initiate S-phase DNA replic­ation.
The G1 and G2 checkp­oints can be regulated by both specific intrac­ellular proteins and extrac­ellular stimuli. In most eukaryotic cells, cell cycle checkp­oints at G1 and G2 are times in which the cell cycle can be arrested, if the previous cell cycle events have not been completed.
The G1 checkpoint will prevent entry into the S or synthetic phase, if DNA mutations or errors are detected.
Progre­ssion from the G2 checkpoint into mitosis may be prevented if the DNA has not been adequately and completely replic­ated, or chromosome separation in mitosis is delayed due to incomplete attachment chromo­somes to the mitotic spindle.

Regulation by specific Protein Kinases

The family of cyclin dependent kinases, CDKs, regulate progre­ssion of the cell cycle by phosph­ory­lating selected proteins on serine and threonine residues.
he cyclin dependent kinases themselves are regulated by complex formation with specific proteins known as cyclins, which bind the kinases and regulate their activity
The are two subsets of cyclins:
The G1 cyclins, which bind to the CDKs during G1 and regulate entry into S-phase
The mitotic cyclins which bind the cyclin­-de­pendent kinases during the G2 phase and regulate entry into mitosis.
One of the charac­ter­istics of the cyclins is the level of cyclins go up and down, i.e., oscillate during the cell cycle.
In contrast the levels of the cyclin­-de­pendent kinases do not change. The cyclin­-de­pendent kinases associate with specific cyclins to trigger various events in the cell cycle. The activity of cyclin­-de­pendent kinases is usually terminated as a result of degrad­ation of the cyclin.
Specific cyclins act in each phase of the cell cycle, for example, there are S-phase cyclins and M-phase cyclins, which in turn form complexes with the cyclin­-de­pendent kinases and trigger cell specific cell cycle events.
In addition to the regulation of cyclin­-de­pendent kinase activity via complex with the cyclins, additional mechanisms exist which regulate cyclin dependent kinase activity.
The cyclin­-cy­cli­n-d­epe­ndent kinase complex can be inhibited by phosph­ory­lation via a protein kinase.
In contrast dephos­pho­ryl­ation of CDK by CDC25 increases cyclin­-de­pendent kinase activity. In addition, the cyclin­-cy­cli­n-d­epe­ndent kinase complexes can also be regulated by binding of a specific inhibitors known as CDK inhibitor proteins.
These inhibitory proteins act primarily in the control of the G1 and S-phase entry. As previously noted, the cyclin­-cy­cli­n-d­epe­ndent kinase complexes are regulated by proteo­lysis of the cyclins at specific stages of the cell cycle. Cyclin destru­ction is mediated by ubiqui­tin­-de­pendent mechan­isms, resulting in proteo­lysis of the cyclin via the proteo­some. The transfer of ubiquitin onto the cyclin is mediated by enzymes known as ubiquitin ligases.
There are 4 specific classes of cyclins, which are defined by the stage of the cell cycle at which they bind their respective cyclin­-de­pendent kinases.
hese are the G1/S cyclins, which work at the end of G1 and commit the cell to DNA replic­ation
the S cyclins, which bind the cyclin­-de­pendent kinases during S-phase, and initiate DNA replic­ation
the M cyclins, which promote entry into and the events of mitosis
Many cells also contain a fourth class of cyclin known as the G1 cyclins which promote entry through the restri­ction point in late G1.

Cell Cycle Control System

The Cell Cycle and Cancer

The control of G1 progre­ssion into S-phase is important because if there is damage to the DNA the cell cycle must pause to allow time for the DNA to be repaired, prior to its duplic­ation in S-phase.
The control of G1 progre­ssion and the initiation of S-phase is often abnormal in cancer cells. If the G1 checkpoint is lost this leads to unrest­rained entry into the cell cycle and consequent cell prolif­era­tion.
Several important tumour suppressor genes, including the retino­bla­stoma gene product and the tumour suppressor gene p53 function to regulate G1 to S-phase progre­ssion. The retino­bla­stoma gene product Rb is an inhibitor of cell cycle progre­ssion, during G1, Rb binds to the transc­ription factor E2F and blocks the transc­ription of S-phase genes.
Cell cycle progre­ssion is also regulated by p53. DNA damage leads to activation of the gene regulatory protein known as p53, which regulates the transc­ription of many important genes, including the cyclin­-de­pendent kinase inhibitory protein p21, which regulates the cyclin­-de­pendent kinases, thereby blocking entry into S-phase.
This delay in entry into S-phase allows the cell time to repair DNA damage, prior to replic­ation of the DNA in S-phase. Should the function of p53 be lost, as occurs in many cancers, over the long term there will be an accumu­lation of genetic damage. Mutation of p53 has been detected in more than 50% of all human cancers.
The G1 checkpoint is a critical checkpoint of no return, cancer cells often abandon the controls, which are present in normal cells, which regulate the G1-S-phase entry.
Once cells exit G1 and progress into S-phase, the cell cycle is automatic.


M-phase, “mitosis” is a phase of nuclear division, which takes approx­imately 1 hour.
During this time the chromo­somes are segregated and two nuclei form.
In cytoki­nesis cytopl­asmic division occurs and the whole cell splits into two. M-phase is charac­terized by progre­ssive compaction of the chromatin (DNA and bound proteins). The DNA is replicated not as bare DNA, but as complex with tightly bound proteins called histones. The condensed chromo­somes segregate onto the mitotic spindle. During mitosis the nuclear envelope breaks down, the nucleus condenses to visible chromo­somes and microt­ubules condense onto the mitotic spindle.
In the middle of mitosis the cell cycle pauses briefly and the duplicated chromo­somes are aligned on the spindle ready for segreg­ation. This may quite often be seen in highly prolif­erative and also malignant cells as mitotic figures. The mitotic index can be used as a marker of the degree of malignancy of the tumour.
During mitosis, mitotic spindles radiate from a body known as the “centr­osome”, which is the major microt­ubule organising centre in the cell. During interphase the centrosome is typically located to the side of the nucleus, embedded within the centrosome are the centri­oles. During mitosis the centriole splits into two and the daughter centro­somes move to opposite sides of the nucleus. Mitosis is organised by the microt­ubule asters, which form around each of the two centro­somes. In mitosis the mitotic spindle aligns the chromo­somes, then each chromosome separates into two daughter chromo­somes.
Each chromosome is aligned by the spindle to the opposite spindle pole. Following mitosis cytoki­nesis occurs during which time the contra­ctile ring of actin forms beneath the plasma membrane and as the ring contracts it pulls the membrane inward to divide the cell into two.


Apoptosis is a physio­logical form of cell death associated with distinct set of bioche­mical and physical changes involving the cytoplasm, nucleus and plasma membrane.
Apoptosis is an important inducible form of cell death involved in the sculpture of structures during develo­pment ie., digits, killing of viral infected cells by cytotoxic T cells, the removal of cells that have unsucc­ess­fully completed mitosis or have unrepa­irable DNA damage, and in general the adjustment of cell numbers.
The balance between the level of cell division and apoptosis is an important determ­inant in cancer. Billions of cells die from apoptosis, and in some cancer cells the level of apoptosis is decreased. For example, billions of cells die in the bone marrow and intestine every hour, in adult humans. In the healthy adult cell death exactly balances cell division resulting in no nett change in organ or tissue size. Some novel therap­eutic experi­mental strategies aim to increase apoptosis in cancer cells.

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