Oncology

Contents

Functions of the p53 Protein

		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]

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]

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

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.

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

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]

• Inefficiency of Metastasis - Although millions of the CTCs have been selected by the primary tumour for some special traits to embark on the long journey, few of them can survive to establish a new colony. Many cancer patients who have recovered from the disease never experience relapse or do so only after a long period of latency. Experiments with injected cancer cells into mice shows the same clinical evidence, i.e., the CTCs fail to form micro-metastases, and only 0.02% form macro-metastases.



	Organ Infiltration - The CTCs can migrate as single cells or as collective ensembles through blood vessels. Eventually, they reach the capillaries, where bio-chemicals are employed to bore path through the extracellular matrix (Figure 21e2), then make its way into the organs. They would use various bio-chemical tricks to bypass the immune responses.
Figure 21e2 Extracellular Matrix [view large image]



• Tissue Defenses against Infiltrating Cancer Cells - The primary tumour cells would develop a co-evolving micro-environment that suppresses immune surveillance and drug treatment. However, this mechanism will not be available once the CTC is detached from this site and would be at the mercy of the defensive responses. To the disseminating cancer cells, every distant soil is deadly except back to the primary site. That's exactly what happens in tumour self-seeding - the most aggressive and drug-resistant clones.


• Metastatic Niches (Figure 21-e3) -

  Native Stem-cell - In native stem-cell niches which are rich in developmental and self-renewal signals such as the bone marrow. Perivascular - Small blood vessels providing lot of supportive signals are also favourate sites. Ad hoc - The disseminated tumour cells (DTCs) can produce components of stem cell niches by themselves, e.g., in breast cancer. Pre-metastatic - Primary tumours can send out signal to create Pre-metastatic niches before the arrival of CTCs. Evidences have shown such influence in the lung, liver, and bone marrow metastases.

  Figure 21e3 Metastatic Niches [view large image]

  
  
• Growth and Survival Pathways - After infiltrating distant tissues, the DTC has to activate and/or amplify some growth and survival pathways to stay alive. As shown in Figure 21e4, it includes :
  
  • Autocrine - It is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell. The signal activates a pathway leading to changes in the cell. Autocrine signaling plays critical roles in cancer activation and also in providing self-sustaining growth signals to tumors.

  Paracrine - It is a form of cell-cell communication in which a cell produces a signal to induce changes in nearby cells, altering the behavior or differentiation of those cells. Such pathway helps to recruit stromal cells as a further source of soluble activators and ampliciers. For example, aberrant activation of the Wnt pathway can lead to increase cell proliferation. Cell-cell Contact - Cell-cell interactions of cancer cells with endothelium determine the metastatic spread. In addition, direct tumor cell interactions with platelets, leukocytes, and soluble components significantly contribute to cancer cell adhesion, extravasation, and the establishment of metastatic lesions.

  Figure 21e4 Metastatic Growth Signaling [view large image]

  
  
• Latent Metastasis - Isolated DTCs most often become latent by entering a state of proliferative quiescence, e.g., in bone-marrow metastasis. In tumour mass dormancy, the metastatic cancer cells fail to grow because of insufficient vascularizaiton or constant culling by immune defenses. It is not sure which mode most frequenctly leads to overt metastases.



• Overt Metastasis - Breaking down growth-inhibitory or immune barriers are the causes in initiating the aggressive metastatic outgrowth of DTCs. The occurrence is often organ specific. For examples, prostate cancer has a propensity to relapse in bone; uveal melanoma tends to recur in the liver; and sarcomas (cancellous bone, cartilage, fat, muscle, vascular, or hematopoietic tissues) often return in the lungs.


• After Therapy - The surgical removal of a malignant tumour is often complemented with radiotherapy and systemic chemotherapy to suppress relapse. If metastasis becomes clinically manifest, most systemic treatments are designed to target metastasis irrespective of

  organ site. Treatments include classic chemotherapy, targeted therapy against oncogenic drivers, immunotherapeutic agents that leverage the antitumour power of the immune system and, increasingly, a combination of all of these. Treatments that target metastasis in a particular organ - by taking aim at cancer-cell interactions with the host tissue - would be indicated when metastasis is confined to that organ, as is the case with bone metastasis in some people with breast cancer. Therapies frequently achieve only partial tumour shrinkage and leave behind substantial amounts of malignant cells. Continued treatment can keep the residual tumour indolent for some time. However, drug-resistant cancer-cell clones eventually emerge that drive rapid relapse. As a result, the cure rates of patients with metastasis remain disappointingly low (Figure 21e5).

  Figure 21e5 Metastasis, Therapy [view large image]

  
  

Causes for the Formation of Carcinoma

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.

		Heredity - It has been noticed that cancers seem to run in some families, about 5 - 10% of the cases is related directly to genetic defect inherited from a parent. Actually, the risk increases substantially only when more than one mutation is involved. It should raise an alarm anyway when two or more first-degree relatives (i.e., parent, sibling, offspring) have tumors in the following conditions :
Figure 21g TP53 Hereditary Defect [view large image]	Figure 21h BRCA1 Hereditary Defect [view large image]	The tumors occur at the same site. The tumors are the same type. The tumors are the rare type.



In general the Family Cancer Syndrome (a collection of symptoms) includes :


• Many cases of uncommon or rare type of cancer, e.g., kidney cancer.
• Cancer occurring at younger ages than usual, e.g., colon cancer in a 20 year old.
• More than one type, e.g., having both breast and ovarian cancer.
• Cancer in both of a pair of organs, e.g., kidneys, breasts, etc.
• Cancer occurring in more than one sibling, e.g., in both a brother and a sister.
• Un-usual occurrence in different sex, e.g., breast cancer in man.


While hereditary defect in the gene causes many diseases such as Down Syndrome, Muscular Dystrophy, ... etc, it is the defecct in tumor suppression gene that is responsible for cancer. The following two examples illustrate the problems :


• Li-Fraumeni Syndrome - At least 140 different mutations in the TP53 gene has been identified some of which have been determined to be harmful, while others as benign or with unknown or uncertain impact. Many of the mutations involve only a single amino acid. Individuals inherited the harmful defects could develop many types of cancers (sarcoma, breast, leukaemia, adrenal gland, ...) and usually at relatively young age (Figure 21g).


• Mutation in BRCA1 and 2 - The BRCA1 and BRCA2 genes in chromosome 17 and 13 respectively also involve in tumor suppression. Individual with defect in these genes carry 75% risk of breast cancer and ovarian cancer although other types are possible as shown in Figure 21h. Why BRCA1 and BRCA2 mutations lead preferentially to cancers of the breast and ovary is not known, it seems to relate to the process of "X-chromosome inactivation" (one copy of the two X chromosomes in mammalian female is rendered non-functional early in the fetus).


• Chemicals - As depicted in Figure 21i, chemical injury could cause cell death, or lead to cancer. Although the chemical induced pathway for cancerous development is not well-understood, the chance of getting cancer by such mean depends on many factors including :

  (1) duration of contact, (2) frequency, (3) when, (4) how, and (5) individual's susceptibility. The U.S. Department of Health and Human Services maintains a "Report on Carcinogens (RoC)" containing hundreds (243 by 2014) hazardous substances (not all of them are chemicals). Examples for some chemical carcinogens are listed in Table 05c below. Most of the entries are in the category of "Known to be Carcinogenic" except Chloroform, which is classified as "Reasonably Anticipated".

  Figure 21i Chemical Causes [view large image]

  BTW, carcinogens are cancer causing substances. Their harmful effects may not be immediate, thus they can be rather insidious.

  
  

  Carcinogen	Sites	Sources
  Arsenic	Lung, bladder, liver, kidney	Smelting, alloys, electrical devices, herbicides, fungicides
  Asbestos	Lung, gastrointestinal tract	Used to be in : roofing, floor tiles, brake linings, textiles
  Benzene	Leukemia, Hodgkin lymphoma	Diesel, printing, paint, (formerly as solvent and fumigant)
  Berylium	Lung	Missile fuel, alloys
  Chloroform	Rectum, bladder, (kidney, liver in animals)	Solvent, reagent, anesthetic, chlorination, pulp/paper mills, waste sites.
  Vinyl Chloride	Liver, brain, lungs, blood, hermangiosarcoma (blood vessel in dog)	PVC plastic, vinyl products

  Table 05c Some Chemicals Carcinogens

  
  

Infections - Cancers from infectious causes is estimated to be at about 15 - 20% worldwide (Figure 21f). The most prevailing infections are caused by the Human papillomvirus, Hepatitis B and C viruses, and Helicobacter pylori with about 30% attributed to each (Figure 21j). These major causes will be commented briefly below. Fungi and parasites can also cause cancers in rare cases. Unlike the causes from genetic heredity, the microbes don't have to alter the cancer suppression genes such as TP53 to hijack the cellular control. Their mechanism is to render the suppressors (suppression proteins) useless.

Figure 21j Cancers by Infections



• HPV Infection - The papillomvirus infect human skin through micro-abrasion in the Basal (Papillary) layer. The infection usually occurs in the anogential region (anus and genitals). Most HPV infections cause no physical symptoms and will heal in few weeks.

  Some cases result in skin warts, and rarely it becomes cancerous with very slow progression in interval of 10 - 30 years. The high-risk infection is a cause for nearly all cases of cervical cancer (Figure 21k). Vaccines has been developed for immunization against the infection. In Canada females 9 through 26 years of age are recommended to take either Gardasil by Merck or Cervarix by GSK. The immunization programs soon ran into controversies as the church equated it to encouragement of early sex, the pharmaceuticals were accused of conspiracy in selling unproven proudcts, and there were rumors about adverse side effects including Multiple Sclerosis (MS) and even death.

  Figure 21k HPV Infection [view large image]

  
  
  Following is a summary of the pathway taking by the virus through the basal cells to develop cancer (also see Figure 21k).
  
  

  Grade 1 - Initially, only a few cells are infected through micro-abrasions in the cervical epithelium. The adoptive immune system of the host usually clears it up in weeks, i.e., within a period similar to recovery of the illness caused by Influenza. At this stage, the viruses try to replicate themselves via activation of the various genes (see Figure 21k, E denotes early expression, L signifies late) in the episomal viral DNA (outside the host's DNA), meanwhile the host's T cells would mount counter-attacks to kill off the virus-infected cells, or to inhibit virus replication.

  Figure 21l Virus Lifecycle [view large image]

  
  
  • Grade 2 - Skin lesions or warts may form at this stage. The adoptive immune responses in a healthy host would eventually win the battle and clean up the combat zone. However, some HPVs may lie dormant for years until the immune system is later compromised in some way, e.g., weaken by aging. In such case, the viral DNA would be integrated into the host DNA, and wait for an opportunity to strike again.
  
  
  • Grade 3 - The progression to cancerous cell is through expression of the viral E6 gene, which would remove the p53 tumor suppessor proteins. Activation of the viral E7 gene creates protein to compete for the pRb (another tumor suppressor protein) binding. The degree to which E6 and E7 are expressed is correlated with the type of cervical lesion that can ultimately develop.
  
  
• HCV/HBV Infections - The HCV, HBV (Hepatitis C and B Virus) together with the Papillomvirus are categorized as "carcinogenic

  	to humans" in the "Report on Carcinogens (RoC)" . While papillomvirus causes tumor in the cervix, HCV and HBV induce cancer in the liver called Hepatocellular Carcinoma (HCC). The virus infection accounts for about 80% of the HCC, which causes 735000 deaths in 2013. The slow development goes through many stages as shown in Figure 21m and summarized below.
  Figure 21m HCV/HBV Infections [view large image]

  
  
  1. Normal State - The liver normally performs many vital functions including : protein synthesis/storage, transormation of carbohydrates, synthesis of cholesterol, production of bile, and detoxification, modification, and excretion of exogenous and endogenous substances. It is also constantly assaulted by various toxins, diabetes, alcohol, and viruses (such as HCV, HBV).
  
  
  2. Fibrosis - The various types of chronic liver injury leave a lot of fibrous scars called fibrosis, which would leadsto portal hypertension (the scarring distorts blood flow through the liver) or cirrhosis (the scarring results in disruption of normal hepatic architecture and liver dysfunction).
  
  
  3. Cirrhosis - Cirrhosis is most commonly caused by alcohol, HCV, HBV, and non-alcoholic fatty liver disease. This is the stage when the patient may become tired, weak, itchy, swelling in the lower legs, develop yellow skin, bruise easily, have fluid build up in the abdomen, or develop spider-like blood vessels on the skin. Scarring in the liver now becomes irreversible, 1 - 5% of the case would develop into HCC.
  
  
  4. HCC - The viruses change DNA mathylation in the hepatocytes (the major cellular population in the liver ~ 80% of its mass) and turn them into malignant tumors. Such alterations affect gene expression and cellular signal transductions including those related to the p53 and pRb proteins. The net result is to promote viral replication and to prevent the cells from apoptosis (programmed death) eventually leading to HCC.
  
  
• Helicobacter pylori Infection - This bacterium was classified as carcinogen by the "International Agency for Research on Cancer" in 1944. They reside in the gut of about 1/2 the world population especial in East Asia. Infected individuals have a nearly eightfold

  	increased risk for Gastric (stomach) cancer (GC). This kind of data mostly came from statistical observations, e.g., more GC cases from individuals infected with H. pylori. It is only recently in the 21st century that some models were proposed to account for the cancer causing mechanisms.
  Figure 21n H. pylori Infection [view large image]	One theory proposes that GC is developed via the interaction between H. pylori and the host genetic susceptibility as explained in the following summary (see Figure 21n).

  
  
  • Chronic Gastritis - About 80% of the infections do not show any symptoms of illness, the rest would progress to chronic gastritis with swelling or inflammation of the stomach lining, or even ulcers.
  
  
  • Astrophic Gastritis - Some of the host's genes involved in digestion such as GASTRIN, HGF etc. possess polymorphisms (~ mutation). The resulting inflammatory action (via expression of the COX2 and iNOS genes) induces atrophic gastritis (chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues). Mutation of the KRas and P53 genes in the process is an essential step in cancerous development.
  
  
  • Intestinal Metaplasia - It is the transformation (metaplasia) of epithelium (usually of the stomach or the esophagus) into a type of epithelium resembling that found in the intestine. The abnormal growth is related to mutation of P53, and environmental factors such as reactive oxygen species (ROS), salt, deficiency of vitamin C, ... etc.
  
  
  • Dysplastia - Continuous assault of such adverse external substances would lead to epithelial anomaly of growth and differentiation - a form of pre-cancerous change in cells and tissues.
  
  
  • Gastric Cancer - Participation of mutant P53 and oncogenes (the gene that has the potential to cause cancer, they are often mutated or expressed at high levels in tumor cells). Activated oncogenes can cause abnormal cells to escape apoptosis paving the way to become cancer.
  
  
  • CagA Strain - It is known that mutation of the SH2 domain in the PTP gene causes myeloid leukemia (abnormal growth of white blood cells). As shown in Figure 21n, a strain of H. pylori with the CagA protein binding to the same domain can cause gastric carcinoma. CagA + is found in majority of the infected East Asians. Specifically, species of CagA+ H. pylori in East Asia exhibit stronger SH2 binding activity and greater pathological activity than those in Western countries. This difference accounts for the different mortality rates (East Asia : North America ~ 10:1) of gastric cancer in these two regions.


• Radiation - The dictionary defines radiation as the process in which energy is emitted as particles or waves. This definition has to be

  		qualified by emphasizing that the particles have to be at high energy ( Mev) and the waves do not depend on a medium (such as the electromagnetic waves, not sound wave which depends on a medium such as air). Thus, radiation is distinct from the energy transfer processes of conduction and convection.
  Figure 21o Sources of Radiation [view large image]	Figure 21p Cancer by Radiation [view large image]

  
  

  As shown in Figures 21o 21p and 21q, radiation can be classified into non-ionizing and ionizing. The dividing line is about 50 ev (Figure 21q), beyond which the radiation will break up cellular structure such as DNA; while the damage is from the generation of reactive chemical by the non-ionizing radiation (Figure 21p). The problem with exposure to a single radiation is minimal whether it is the high or low energy variety. The cell has mechanism (such as committing suicide as directed by the p53 protein) to deal with that. It is the does in term of energy per unit mass or unit volume or unit area that inflicts the damage according to the the amount and duration of exposure. The following is a brief description for these two kinds of radiation.

  Figure 21q Radiation Energy

  Non-ionizing Radiation - The harmful non-ionizing radiation is mostly referred to the ultra-violet light (UVC, B, A) from the Sum. The higher frequency UVC is mostly blocked by the ozone layer (there may be holes in this era of global warming). UVB and UVA are the two bands that can penetrate to the basal and dermis respectively (Figures 21o and 21r). Normally, penetration of radiation is proportional to its energy. The relationship is reversed in the UV radiation. It turns

  Figure 21r Non-ionizing Radiation [view large image]

  out that reflection plays a dominant role in this case. Thus, UVB (the one with higher energy) would do damage only down to the basal layer while UVA goes deeper into the dermis.

  
  

  The intensity (dose) of UV radiation is measured in the units of milliwatts per cm2 (mW/cm2). Canadian scientists invented the UV index from the typical dose of 250 mW/m2 in midday summer sunlight (the highest dose in Canada) by dividing 25 mW/m2 to generate a convenient range for the UV index with a scale of 0 to 11 (see table 05d). It is now broadcasted daily in Canada as part of the weather forecasts.

  Table 05d UV Index [view large image]

  
  
  • Ionizing Radiation - There are many sources of ionizing radiation as shown in Figure 21o :
    • Cosmic Rays - These are very high energy particles (up to 10¹⁰ Gev) from outer space. They are transformed into air shower in the upper atmosphere. The rate is very low at about 1 particle/km²-sec. Solar storms are local cosmic rays released by the Sun, they may disrupt telecommunications but would do no harm to humans.
    • Radon Gas - It is the by product of radioactive decay on Earth. Its harmful effect can be minimized by better ventilation in the building.
    • X-ray - The medical scan produces very low dose and should not be a problem unless with frequent exposures.

    		Nuclear Fallout - It is the radioactive material produced by nuclear blast or nuclear reactor accident. The effect of nuclear testing has been mitigated somewhat by the "Test Ban Treaty", which some countries have yet to ratify and a few had conducted their own tests anyway. There were a few nuclear accidents, the latest one occurred in Fukushima, 2011.
    Figure 21sa Ionizing Radiation	Figure 21sb Annual Radiation Exposure [view large image]

    
    Figure 21sb shows the annual background radiation exposure from different sources. The radon used to be the major contributor, but medical scan becomes the leading source in developed countries over the years with modern medical procedures. The safety threshold recommended by The International Agency for Research on Cancer (IARC) limits exposure to 20 mSv annually over 5 years, with a maximum of 50 mSv in any one year.
    
    The unit for radiation dose in Roentgen was originally defined in 1928. It is the energy to produce 2.1 x 109 ion pairs in a volume of 1 cubic centimetre of air, which is equivalent to about 100 ergs per gram of water or tissue irradiated. Although it seems to be a minute amount of energy when one considers that 42 million ergs are required to raise the temperature of 1 gram of water by 1^oC. The remarkable property of ionizing radiation is that the small amount of energy represented by a few hundred rontgens can kill a person. For low level irradiation, the effect is similar to premature aging depending on doses and duration of exposure. In the U.S., the National Institute of Standard and Technology (NIST) strongly discourages the use of Roentgen as it is not really a SI unit. Another SI unit called Sievert (Sv = 1 J/kg = Gy) is now widely used in medical circle to measure the biological effects (1 rad = 0.01 Sv = 10 mSv). Figure 21sa lists the adverse symptoms related to the levels of radiation (in Sv).
  
  
• Other Causes - It is mostly about un-healthy lifestyles as listed below :
  
  
  • Smoking - As shown in Figure 21t smoker inhales a host of chemicals harmful to health leading to various diseases including

    	cancer. It is found that the poisons can weaken the body's cancer suppression mechanism allowing the cancerous cells to grow out of control. Smoking can cause cancer almost anywhere in the body, but most often occurs in the upper respiratory tract - the smoke's thoroughfare. The poisons eventually congregate inside the lung where 9 out of 10 cancers are caused by smoking cigarettes.
    Figure 21t Cancer by Smoking [view large image]

    
    
  • Alcohol - Alcohol (Ethanol) is harmful via its metabolites - the products of various chemical (metabolic) processes inside an organism. They inflict damage on DNA, cause malfunctioning of the body, and eventually become carcinogenesis as outlined briefly below.

    The most harmful metabolites are the acetaldehyde and acetic acid, which can damage both DNA and proteins. It can produce reactive oxygen species, which can damage DNA, proteins, and lipids (fats) through a process call oxidation. Alcohol can impair the body's functions including the absorption of nutrients and the various kinds of vitamins. It increases the blood levels of estrogen, which is a sex hormone linked to the risk of breast cancer.

    Figure 21u Cancer by Alcohol [view large image]

    As shown in Figure 21u, the carcinomatous sites are mostly along the digestive tract, where the alcoholic drink passes through. See "The Effects of Alcohol and Alcoholism on Your Health" for impacts on the other organs.

    
    
  • Diet - There are numerous cellular mechanisms for food processing in our body. Defect of the "methionine metabolic pathway" stands out as the cause of carcinogenesis. This process is shown in cartoon in Figure 21u. Essentially, the process

    	at the end add a methyl group to the DNA (called methylation), or RNA, or proteins. The addition has a profound effect on gene expression, the deficiency of which often leads to cancer. Some of the foods for enhancement of methylation are shown in Figure 21u. The soybean also serves to increase the activity of the P53 - the tumor suppression gene.
    Figure 21v Methylation of DNA [view large image]	In this image, SAM stands for S-Adenosyl methionine, which is a common cosubstrate (cofactor, helper molecule) involved in methyl group transfers, transsulfuration, and aminopropylation.

    
    
  • Obesity - The Body Mass Index (BMI) provides a rough measurement to determine whether an individual is under-, normal, or over- weight. It is defined by the formula BMI = (weight in kg)/(height in m)² = [(weight in lb)/(height in inch)²]x703. Figure 21w shows the various characterizations under different range of the index. An individual with BMI 30 is considered to be obese. This is a rich man's disease as shown in the world obesity map. Several possible mechanisms have been proposed to explain the association of obesity with increased risk of certain cancers (see below and Figure 21w).
    
    

    Fat tissue produces excess amounts of estrogen to elevate the risk of breast, endometrial, and other types of cancer. Increased levels of insulin insulin-like growth factor-1 in blood may promote the development of certain tumors. The adipokines hormones produced by fat cells may cause abnormal cell growth. The fat cells have an unknown effect on the TOR protein, which regulates the growth of organisms including the growth of tumors.

    Figure 21w Cancer by Obesity [view large image]

    
    

  The flip side of the cause is prevention. It is the practice of avoiding those causes that lead to the development of cancer. The Mayo Clinic puts it into 7 tips : Don't use tobacco. Eat a healthy diet. Maintain a healthy weight and be physically active. Protect yourself from the sun. Get immunized. Avoid risky behaviors, i.e., practice safe sex. Get regular medical care (especially for the case of genetic heredity).

  Figure 21wb List of Risks [view large image]

  Figure 21wb summerizes some of the risks, real and imagined. Two more popular misconceptions about harmful substances : (1) Genetically Modified (GM) foods, (2) Drinking from plastic bottles.

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  Symptoms

  
  

  There is no single marker that indicates the occurrence of cancer. In general, please take note when you feel something abnormal in your body (symptom) or an unusual appearance is detected (sign). A single signal (symptom or sign) by itself may not mean anything serious. However, please check it out with your doctor if many signals happen simultaneously and last for a long time or get worse. Cancer is easier to cure when it is treated earlier. The signs and symptoms in the followings (and in Figure 21x) are just a rough guide. Don't be over alarming, sometimes the mere thought of having cancer is enough to wreak havoc with one's health.

  Figure 21x Signs and Symptoms of Cancer [view large image]

  
  
  The signal can be localized (in certain part of the body) or systemic (concerning the whole body). Different type of cancer may present different signal. It may indicate early or advanced stage. Here's some of them (the list is not exhausted) :
  
  
  1. Unexplained Weight Loss - Weight loss of 10 pounds or more for no known reason may be the first sign of cancer. It happens most often with cancers of the pancreas, stomach, esophagus, or lung. Cancer patients may also experience loss of appetite (anorexia) because cancer can affect food tastes or makes it un-appealing.
  
  
  2. Fever - It is very common with cancer (but also very common with other diseases). It could occur at advanced stage when the cancer has spread. The early stage fever could be associated with leukemia or lymphoma when the immune system has been compromised.
  
  
  3. Fatigue - In general, cancer sucks away the body's nutrient causing extreme tiredness that doesn't get better with rest. It could be associated with early stage of leukemia. Another cause may be hidden blood loss in colon or stomach cancer.
  
  
  4. Pain - Pain may be an early symptom with bone or testicular cancer. Persistent headache could mean brain tumor. Back pain could be related to colon, rectum, or ovary cancer. Most often, pain means that the cancer has metastasized (spread) from where it started. Usually, pain is generated when the nerve is compressed by cancerous overgrowth.
  
  
  5. Night Sweats - Night sweats are an early symptom of some cancers. The most common type of cancer associated with night sweats is lymphoma.
  
  
  6. Nausea and Vomiting - This is a very common condition in minor ailments. This is mostly associated with brain cancer when it fails to heal. It is suspected that such symptoms are controlled by the part of the brain called the vomiting center.
  
  
  7. Skin Changes - The occurrence of any wart, mole, or freckle that changes color, size or shape (with no sharp border) is a definite sign of skin cancer (see a doctor quick before it goes down into the dermis). Other kinds of cancer also induce skin change such as :
     • Sudden development of darker look skin (hyperpigmentation) Melanoma (skin cancer).
     • Yellowish skin and eyes (jaundice) Live cancer.
     • Reddened skin (erythema) Lung cancer.
     • Itching (pruritis) Lymphoma.
     • Excessive hair growth Ovarian cancer.
     
     
  8. Lump in the Body - A lump could be a sign of cancer at all stages especially when it grows in size. It is most common in breast, testicle, or lymph nodes (glands).
  
  
  9. Long-Lasting Sores - It could be skin cancer. It would be oral cancer if the sore is in the mouth - especially for smoker.
  
  
  10. Change in Bowel Habits or Bladder Function - Long term constipation, diarrhea, or change in the size of the stool may be a sign of colon cancer. Pain with urination, blood in the urine, or abnormal bladder function could be related to bladder or prostate cancer.
  
  
  11. Unusual Bleeding or Discharge - Bleeding can occur in all stages of cancer. It is a common sign in :
      • Lung cancer coughing up blood (hemoptysis).
      • Colon or Rectal cancer blood in stool (in very dark color).
      • Cervix or Uterus cancer vaginal bleeding.
      • Bladder or Kidney cancer blood in urine.
      • Breast cancer bloody discharge from the nipple.
      
      
  12. Nagging Cough or Hoarseness - A cough that does not go away may be a sign of lung cancer. Hoarseness can be a sign of cancer of the larynx or thyroid gland.
  
  
  13. Dyspnea - While shortness of breath is a very common sign with minor ailments, it could be a signal of lung cancer.
  
  
  14. Hepatomegaly - It is the condition of having an enlarged liver - a sign of liver cancer.
  
  
  15. Indigestion or Problem with Swallowing - It could be the sign of esophagus, stomach, or throat cancer. Most often, it is caused by something else.

Diagnosis

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]

• Lab Tests - The high or low or abnormal level of certain substances in the body may be a sign of cancer. The following three types of fluids are usually involved in the tests.


• Blood Test - It tries to detect
• the high, low, abnormal amount of certain blood cells.
• presence of certain abnormal immune system proteins.
• chemical markers made by cancer cells.
• detached cancer cells in the bloodstream.


• Urine Test - It is often done when blood is present in the urine. It looks for
  • abnormal cells which could be related to inflammation instead of cancer.
  • cancer cells in the urine (cytology).
  • level of the proteins AQP1 and PLIN2 in kidney cancer.
  
  
• Body Fluid Test - This is cytology involving fluid inside the body cavity including sputum (phlegm), spinal fluid, pleural fluid (around the lung), pericardial fluid (from the sac that surrounding the heart), and ascitic fluid (from the spaces in the belly). It is sometimes performed with just scraping a small amount of tissue from a body part such as from the cervix in the Pap test.

Image Scanning - Since different organ inside the body cavity has different density, it responses differently to the impact of radiation.

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]

• CT Scan - This is an X-ray machine working together with a computer to produce a 3-dimensional image. The patient receives a dye or other contrast material to highlight the organ inside the body. As shown in Figure 21x1, the detector is opposite to the X-ray source; the whole thing is rotating while the object passing through the ring. The procedure is fast, painless, non-invasive and accurate. There is no conclusive evidence that radiation at small amounts delivered by a CT scan causes cancer.


• PET Scan - This test exploits the way that the body handles substances differently when there is disease or pathology present. The radioactive material (tracer) introduced into the body is often chemically bound to a complex that acts characteristically within the body. The concentration appears as a "hot spot", the "cold spot" is produced by the kind of diseases which exclude the tracer. The direction of the radiation is from inside to a ring of detectors surrounding the patient outside (see image in Figure 21x2). The potential health risks from radiation exposure are low compared with the potential benefits. There are no known long-term adverse effects from such low-dose exposure.


• MRI - The strong magnetic field in the machine aligns the tiny magnets in the water molecules. Since different organs contain different water concentration, they would produce different amount of electromagnetic signals when the alignments are disturbed by radio waves. A computer would generate a 3-dimensional image accordingly with special software to analyse the signals. MRI scanning is painless and does not involve exposure to high energy radiation. However, patients with heart pacemakers, and other types of metal implants cannot be scanned with MRI because of the effect of the magnet. MRI scan should be the best choice for imaging the body cavity if it is not so expensive.



Ultrasound - It uses high frequency sound wave to probe organs inside the body cavity. The reflected waves (the echo) are analyzed by computer to create a picture of the area inside. Since the reflection depends on the density and composition of the object, the patient may have to swallow something to make better contrast. There may be problem with ultrasound scan during pregnancy. Actually all kinds of scans carry some risk for the embryo in the womb.

Figure 21x3 Ultrasound Scan



• Biopsy - This is the medical test by taking tissue or fluid from the patient for examination. The tool can be just a needle or a more troublesome endoscope (Figure 21x1). Surgery is the most invasive technique. The excision may inflict harmful consequence especially for elderly patient. Recent (2016) research on liquid biopsy (Figure 21x4) is one way to address such problem.

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]

To summarize (also see Figure 21x4) :


• Circulating Tumour DNA - Digital Polymerase Chain Reaction (dPCR) allows researchers to detect or quantify pieces of tumour DNA at levels as low as 0.1% of the total in the blood. However, this method is restricted to known sequence of the aberrant DNA. The next-generation sequencing (high-throughput sequencing) is more useful to look for DNA mutations. It is found that tumour DNA fragments are usually shorter than the normal making it an easy way to check out metastasis or spotting relapse. The presence of tissue specific markers (like the histone packaging) may yield information about the location of the cancer.


• Circulating Tumour Cells - It seems that counting tumour cells in the blood is not a reliable indicator. The number does not always reflect the aggressiveness of the cancer. However, sequencing the DNA or RNA in such cells may provide more insight into the nature of gene alterations.


• Exosome Exam - Exosomes are tiny vesicles shed by all living cells, including tumours. They contain DNA, RNA and proteins. The isolation of such substances are more challenging than the other methods. The presence of a particular exosome can be captured by antibody in certain type of assays such as the nPLEX.


• Platelets Exam - It has been observed that platelets in the blood can swallow vesicles loaded with tumour RNA, which looks markedly different in the 39 people who had early-stage cancers. The tests had been extended to 1000 people with 10 different types of cancer and developed into a power tool as part of liquid biopsies.

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

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Treatments

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]

Treatment starts with diagnosis, which involves medical tests including blood tests, X-rays, CT scans, endoscopy, and biopsy (cutting a piece of tissue from the malignant site). From the result of the test(s), the type treatment(s) will be determined together with other factors such as stage of the cancer, the patient's health, socioeconomic setting, ... Common side effects caused by cancer treatment include : anemia, appetite loss, bleeding and bruising, constipation, diarrhea, edema, fatigue, hair loss, infection, lymphedema, memory/concentration problems, mouth ant throat problems, nausea and vomiting, nerve problems, pain, sexual and fertility problems, skin and nail changes, sleep problems, urinary and bladder problems. These kinds of discomfort will eventually disappear if the treatment is successful. The following describes briefly the types of treatment available today :



• Surgery - Most cancer patients will go through some kind of surgery from diagnosis to restoration of the body's appearance or function.

  		This form of treatment is most suitable when the cancer is contained in one area. The lofty goal is the complete removal of the cancer without damage to the rest of the body - a miracle that is seldom achieved.
  Figure 21za Lobectomy, Mastectomy [view large image]	Figure 21zb Colectomy, Nephrectomy [view large image]

  
  
  The surgical operation may involve steps such as :
  
  
  • Anesthic is administered to stop the sensation of pain.
  
  
  • Blood vessels may be clamped or cauterized (burned) to prevent bleeding.
  
  
  • Incision or resection is performed to completely or partially remove the affected organ (see Figure 21za, where the suffix -ectomy means removal and the prefix is the name of the organ - all in Greek).
  
  
  • Reconnection of the body part (if that's possible) as shown in Figure 21zb.
  
  
  • Cleaning up the mess at the end of the operation.
  
  
  Modern techniques (Figure 21zc) allow the surgery to be less invasive and more precise (in targeting the tumor), for examples :
  
  

  Laser Surgery uses laser beam via fiber optics and special scope to pinpoint and to destroy cancers of the cervix, lung, skin, or other organs. Cryosurgery directs liquid nitrogen to kill the cancer in liver and prostate by extreme cold temperature. It is sometimes used to treat pre-cancerous skin, cervix, and penis. Electrosurgery destroys the skin or mouth cancer by high-frequency electrical current. Radio Frequency Ablation (RFA) is sent through a needle to heat and destroy the cancer cells in the liver, lungs, kidney, and other organs. Mohs surgery is used to remove certain skin cancers by shaving off one very thin layer at a time until the normal one. Laparoscopic surgery employs a long, thin, flexible tube to probe inside the body. It can be used to help the removal of many types of cancer.

  Figure 21zc Modern Surgical Techniques [view large image]

  
  
• Radiation Therapy - It uses ionizing radiation to kill tumor cell by breaking up its DNA. It also damages the surrounding tissue indiscriminately. Modern innovation adds an intensity modulated device to focus the radiation beam more precisely to its target, and sometimes employs multiple beams aimed from several angles of exposure to intersect at the tumor providing a much larger dose.

  This is shown schematically in Figure 21zd where IMRT stands for Intensity Modulated (controlled) Radiation Therapy, while the "P" in IMPT denotes the use of high energy "Particle" instead of "Radiation". Actually, the radiation dose (in unit of Gy = J/kg) is limited by the radiation tolerance of the various organs. Table 05e lists the tolerance dose to an organ based on giving the dose in one fraction or fractionated, using TD5/5 (5% chance of injury showing up over the next 5 years) and TD50/5 (50% chance of an injury in next 5 years).

  Table 05e Parameters of Radiation Therapy : Tolerance Doses (TD5/5 - TD50/5)

  
  

  Radio-sensitivity is defined as the does required to kill the tumor. While the cancer cells in leukemias and lymphomas can be eliminated rapidly by radiation, killing of epithelial cancers need a moderate does (60 - 70 Gy) to be effective. Renal cancer and melanoma are radio-resistant, radiation therapy is just a palliative option (not intended to cure, but only for the lessening of suffering) for terminally ill patients. Since large size tumor does not respond well to radiation therapy, surgery or chemotherapy is often performed prior to the radiation treatment.

  Figure 21zd Radiation Therapy [view large image]

  Radiation "curability" is not exactly the same as radio-sensitivity. For example, leukemias are not curable with radiation therapy because the cancerous cells spread all over the body, while lymphoma is basically curable if it is localized to one area of the body.

  Side Effects :
  
  
  • Acute - nausea and vomiting, damage to the epithelial surfaces, mouth/throat/stomach sores, intestinal discomfort, swelling, infertility.
  
  
  • Late - fibrosis, epilation (hair loss), dryness, lymphederma, cancer, heart disease, congnitive decline, radiation proctitis (inflammation of the rectum and anus).
  
  
• Chemotherapy - Most chemotherapeutic drugs work by disrupting the cell division of the tumor. As shown in Figure 21ze, its action can be stopping the cell division, causing cell death or interfering with the blood supply. Since the killing process of chemotherapy proceeds in much slower pace than surgery and radiation therapy, the cancer cells have time to react to such assault by various strategies including : (1) removing the chemotherapeutic drugs, (2) gene amplification to increase the number of gene expression, (3) modification of the cellular pathways to avoid apoptosis, (4) secreting enzymes to repair DNA damage, and (5) mutation of membrane receptor to prevent binding of chemo drugs. Numerous researches are on going to overcome these kinds of resistance.
  
  

  Another problem with chemotherapy is the indiscriminate killing of all actively dividing cells whether they are normal or cancerous. However as shown in Figure 21ze, the killing effect on normal cells requires higher dose and thus creates a safety window within which more than 50% of the normal cells would survive while up to 80% cancerous cells may be eliminated. Targeted therapies use relatively new class of drugs to target certain special features in the tumor. These kinds of drug are cancer type specific, or even on patient specific basis. Therapeutic dosage depends on the kind of drug and body specific parameter such as metabolic mass or body weight. For many clinical purposes a more suitable indicator is the Body Surface Area (BSA) defined by BSA (in m2) = [(height in cm)x(weight in kg)/3600]1/2 (see "Chemotherapeutic Agents and Their Uses, Dosages, and Toxicities" about the determination of dosage for different kinds of drug).

  Figure 21ze Chemotherapy [view large image]

  The choice for specific drug depends on : (1) type of cancer, (2) stage of the cancer, (3) patient's health. Most chemotherapy is delivered intravenously, about 10% is given orally (Figure 21ze).

  
  Side Effects : immunosuppression (immunity suppression), myelosuppression (bone marrow suppression), typhitis (inflammation of the cecum), gastrointestinal distress, anemia, fatigue, nausea/vomiting, hair loss, secondary neoplasm (abnormal growth of tissue), infertility, teratogenicity (fetal malformation), cognitive impairment, tumor lysis syndrome, organ damage.
  
  
• Other Cancer Treatments -
  

  Immunotherapy - Essentially, this method uses the "Adaptive Immune System" and specifically the T cells to kill the tumors as each one presents an unique antigen. The T cell with the corresponding antibody would lock onto the antigen and execute the cancer cell. As shown in Figure 21zf sometimes the cancer cell would counteract by activating the CTL-4 surface protein via which the killing action is inhibited. Immunotherapy would counter-attack by attaching the Yervoy antibody on the T cell to nullify the blocking. In general, artificial antibody made in laboratory can be used to : (1) make the cancer cell more visible to the immune system, (2) block growth signals to the cancer cell, (3) stop new blood vessels from forming, (4) deliver radiation or chemotherapy to cancer cells. These so called monoclonal antibodies are administered through the vein intravenously. There are non-specific immunotherapies such Interferons, and Interleukins to boost up the immune system. Vaccines are also available to prevent occurrence or recurrence of certain types of cancer. Hyperthermia - It destroys small patch of tumor with very high temperature produced by microwave, radiofrequency, or ultrasound. It can be administered externally, intraluminally (via a probe), or interstitially. Another approach is to raise the body temperature (to 107oF) using thermal chambers (similar to large incubators) or hot water blankets. It is used to treat metastatic cancer together with other treatments such as radiation, chemotherapy, or immunotherapy. Stem Cell Transplant - Healthy stem cells of the cancerous organ are removed and stored in the laboratory before cancer treatment and re-introduced back afterward. Photodynamic Therapy (PDT) - This method injects special drugs called "photo-sensitizing agents" into the bloodstream. It is absorbed by cells including the cancer cells over a period of time. The drug is activated by light pointing the specific area, it reacts with oxygen to produce chemical that kills the tumor.

  Figure 21zf Other Cancer Treatments [view large image]

  
  
  Advantages :
  • No long-term side effects.
  • Less invasive.
  • Duration of treatment is short and can be done as outpatient.
  • Precise targeting.
  • Allow repeated treatments.
  • No scarring after healing.
  • Cost less.
  
  
  Disadvantages :
  • Treatment area is limited by accessibility of light.
  • Useless for metastatic cancer.
  • It leaves the patient very sensitive to light for some time.

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

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