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Functions of the p53 Protein
Differences Between Normal Cell and Tumor
Causes for the Formation of Carcinoma :
          (Heredity, Chemicals, Infections, Radiation, Others)
Symptoms of Cancerous Growth
          (Lab Test, Image Scanning, Biopsy)
Treatments for Cancers :
          (Surgery, Radiation Therapy, Chemotherapy, Other Treatments)

Functions of the p53 Protein

The p53 protein can suppress the formation of abnormal cell. Its corresponding gene P53 (TP53 in human chromosome 17, note the capital letter for gene, protein is denoted by small letter) is in-activated by the mdm2 regulator in normal circumstance. It is expressed upon the detection of DNA damage or abnormal cell growth (actually the amount of p53 in the cell follows a damped osciallation pattern). As shown in Figure 21c1, functions of the p53 proton include cell cycle arrest (stopping cell division), DNA repair, and apoptosis (cell suicide). Other actions may also be initiated depending on the presence of different intermediate protein (transactivator) in different environment, e.g., in different type of tissues. The p53 protein also presents itself in 12 different forms (isoform) making the process very complicated. Figure 21c2 shows some responses of such myriad products. The p53 is not the only cancer fighting protein, other tumor suppressors such as the pRb protein (controlling cell division) are also know. Anyway, if the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood. The TP53 gene can also be modified by mugtagens (chemicals, radiation,
p53 Pathway p53 Functions or viruses), increasing the likelihood for uncontrolled cell division. More than 50% human tumors contain a mutation or deletion of the TP53 gene. Pharmacological research is on going to re-introduce p53 endogenously (by adenovirus) as a viable cancer treatment. China has approved such clinical treatment for the "head and neck squamous (scale-like) cell carcinoma" in 2003.

Figure 21c1 p53 Pathway

Figure 21c2 p53 Functions [view large image]

Extra P53 Copies in Elephant Why elephants do not get cancer is a famous conundrum that was posed in the 1970s (Figure 21c3). Scientists were bewildered as to why they don't get the disease despite having 100 times as many cells as humans and hence about 100 times more chance. Two independent researches have revealed in 2015 that their chromosome carry 20 copies of the P53 gene while human has only one. They have a more robust mechanism for killing damaged cells that are at risk for becoming cancerous. It remains to be checked out if other massive animals such as whales also possess more copies of this P53 gene. See "How elephants avoid cancer" in Nature, 08 October 2105.

Figure 21c3 Extra P53 Copies in Elephant [view large image]

It seems that a good way to prevent the development of cancer would be to have plenty of p53 proteins in the body everywhere. It turns out that
P53 Shield too much of the good thing becomes lethal causing death. Mice with too much of p53 die within one day owing to unchecked cell death in the brain and severe neurological defects. On the other hand, mice lacking p53 gene die within two weeks of birth. It has been discovered in 2016 that there is a tightly controlled system to regulate the activity of p53. As shown in Figure 21c4 at time of cell stress, acetyl group (Ac, acetylation) are added to the CTD domain of p53 allowing it to target the DNA (via the CBT or p300 protein). The subsequent gene transcription would influence the cell fate (cell cycle arrest, DNA repari or cell suicide). In case there is no stress, the SET protein would bind to the CTD removing the intermediate link via the CBT or p300 so that no transcription is processed and no harm is done to the cell.

Figure 21c4 p53 Shield
[view large image]

See original article : "Acidic Shield Puts a Chink in p53's Armour".


Differences Between Normal Cell and Tumor

Cancer Everyone has a chance of harboring precancerous cells. Thank to the numerous checkpoints within the cell, only about 2.5% of Canadians had been diagnosed with cancer in the previous 10 years (according to a 2009 survey). Based on 2006-2008 estimates, 63% of Canadians diagnosed with cancer are expected to survive for 5 years or more after a cancer diagnosis. Grading of the disease depends on whether the cells are differentiated (low grade) or undifferentiated (high grade = severe) as depicted roughly in Figure 21d2.

Figure 21d1 Cancer
[view large image]

Figure 21d1 shows the cancer cells under microscope (a) and through speculum (b). Some of the differences between normal cell and tumor are shown in Figure 21d2 and Table 05b below.

Normal Cell vs Tumore
Property Normal Cell Tumor
Growth Receive message from neighbor to stop Ignore message, keep on growing
Repair Either repaired or die No repair and no apoptosis
Spread Stick to its neighbor No adhesion, free to roam (metastasize)
Appearance Maintain regular shape and size Varied shape and size with large nucleus
Maturation Mature to various functional types Immature, undifferentiated and immortal
Control Controlled by cellular processes Evade detection and inactivate enforcement
Angiogenesis Blood vessels are limited by necessity Hoarding blood vessels

Figure 21d2 Normal Cell vs Tumor [view large image]

Table 05b Normal Cell vs Tumor

The telomeres lie at the tips of the chromosome. They have hundreds to thousands of repeats of a specific 6-nucleotide DNA sequence. The telomeres lose 50 to 200 of these nucleotides at each mitosis; gradually shortening the chromosome. After about 50 divisions, a critical amount of telomere DNA is lost, which somehow signals the cell to stop mitosis. The cell may remain alive for a while but is unable to divide further. This process of telomere shortening has been likened to a biological clock that winds down to eliminate unhealthy old cells (Figure 21d3,d).
Telomere Lengthening A 2016 research report indicates that some cancer cells avoid this fate through a mechanism called "Alternative Lengthening of Telomeres" (ALT). The process is summarized in Figure 21d3 : (a) Shortening of telomere in normal cell division. (b) The cancer cell produces a protein complex RFC1-5 and binds it to the break. (c) The RFC1-5 recruits more enzymes to replicate the telomere from a template.

Figure 21d3 Telomere Lengthening

The discovery may lead to future therapies to kill cancer cells by targeting the ALT.
See "DNA repair: Telomere-lengthening mechanism ".



Metastasis Cancer cells start early to metastasize by entering circulatory system long before a tumor is diagnosed. These circulating tumour cells (CTCs) seldom survive due to immune resistance. However, few of them may evade suppression and stay in niches to re-activate again in favorable condition. Figure 21e1 depicts the various events leading to overt colonization. The relapse can occur in distant site and the latency can last from months to decades. Details of the process can be found in the original article "Metastatic Colonization by Circulating Tumour Cell" in Nature, 21 January 2016. The long article is summarized in a few steps below :

Figure 21e1 Metastatsis
[view large image]


Causes for the Formation of Carcinoma

Causes of Cancer The ultimate cause for cancer is the failure of cellular control on the growth and development. The problems could be genetic (5-10%) or environmental as shown in Figure 21f. The genetic (hereditary) cause can be further classified by occurrence in different organs together with family risk ratio. There are many environmental causes, each one is labeled by its percentage contribution.

BTW, the risk ratio R is defined by the formula R = (SE/NE)/(SC/NC), where S stands for number of occurrences, N for the number of participants; the subscripts E and C denote the experimental and control group respectively. For the special case of NE = NC , R = SE/SC . The experimental (clinical trail) group in Figure 21f is the family members with history of particular cancer.

Figure 21f Causes of Cancer
[view large image]

The various causes are under slightly different headings according to different literatures. The following list should cover most of them.



Cancer Diagnoses To address the lagging doubt about the symptoms, it is advisable to run a diagnosis to determine the cause. There are many types from body fluid testing, image scanning, to the more invasive biopsy. The test usually tries to detect some molecular markers shedding off the tumor cells or by examining the lump directly. The diagnostic tools can be summarized into three categories as shown in the followings (also see Figure 21x1).

Figure 21x1 Cancer Diagnoses
[view large image]

  • Image Scanning - Since different organ inside the body cavity has different density, it responses differently to the impact of radiation.
    Image Scanning Some scanning techniques depend on different affinity of the organ to radioactive material to become the source of emission from within. Regardless of the methods, the test requires skillful technician (radiologist) to detect the tumor by its abnormal disposition or by comparison with previous image (for recurrence). Figure 21x2 shows two images produced by two different type of scanning machines. The lumpy growth is apparent by its size, while tiny spot in recurrence is more difficult to detect. There are several techniques as listed in the followings.

    Figure 21x2 Image Scanning
    [view large image]

    Liquid Biopsy The discovery that parts of tumour cell, or even a whole cell, break away from the original site and enter the bloodstream led to the idea of liquid biopsies. With this approach, cancers can be genetically characterized by analyzing tumour DNA taken from a blood sample, thus bypassing the need to extract solid tumour tissue. The biopsy becomes a type of blood test albeit more sophisticated. It is the rapid rise of genome-sequencing techniques that has made it practical to translate the concept to the clinic. Information about the sample can be obtained from the tumour cell, its DNA, the exosome, or even the platelets (Figure 21x4). Researchers suggest that it is no longer a question of whether liquid biopsies will one day replace surgical biopsies, but when and in what form. This technique may have a problem with locating the tumour.

    Figure 21x4 Liquid Biopsy
    [view large image]

    See original article in "The Tumour Trail Left in Blood" for details.



    Cancer Survival Rate There are many types of cancer treatment. Some of them are invasive while the others may entail adverse side effects. Figure 21y shows the 5 years survival rate after diagnosis (and following up with treatment). Some types of cancer such as the one in the prostate has excellent chance of about 100% since it mostly occurs in very old age and is usually harmless. While the pancreatic cancer is the most lethal with only about 5% survival rate. This type of cancer typically spreads rapidly and is seldom detected in its early stages. As shown in Figure 21y (the percentage within brackets), the survival rate drops rapidly once the cancer has metastasized.

    Figure 21y Cancer Survival Rate
    [view large image]

    Finally, see more information about cancer in "National Cancer Institute".

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