Topic 1- Introduction to Cancer biology
Cancer biology encompasses the application of systems biology approaches to cancer research,
in order to study the disease as a complex adaptive system with emerging properties at multiple
biological scales.
Introduction
Cancer systems biology therefore adopts a holistic view of cancer aimed at integrating its many
biological scales, including genetics, signaling networks, epigenetics, cellular behavior,
histology, (pre)clinical manifestations and epidemiology. Ultimately, cancer properties at one
scale, e.g., histology ( cell behavior).
The fundamental concept is that percolation of properties across scales must be measured and
taken into account in order to fully understand etiology, progression and dynamics of cancer. The
systems biology approach relies heavily on the successes of decades of reductionism, which has
clarified the component parts and mechanistic principles of living organisms, as well as their key
alterations in cancer, especially at the genetic/genomic scale, to deep detail.
Basic researchers and clinicians have progressively recognized the complexity of cancer and of
its interaction with the micro- and macro-environment, since putting together the components to
provide a cohesive view of the disease has been challenging and hampered progress. Cancer
biology merges traditional basic and clinical cancer research with “exact” sciences, such as
applied mathematics, engineering, and physics. It incorporates a spectrum of “omics”
technologies (genomics, proteomics, epigenomics, etc.) and molecular imaging, to generate
computational algorithms and quantitative models that shed light on mechanisms underlying the
cancer process and predict response to intervention.
Cancer
Definition
Cancers are a large family of diseases that involve abnormal cell growth with the potential to
invade or spread to other parts of the body. They form a subset of neoplasms. A neoplasm or
tumor is a group of cells that have undergone unregulated growth and will often form a mass or
lump, but may be distributed diffusely.
All tumor cells show the six hallmarks of cancer. These characteristics are required to produce a
malignant tumor. They include:
Cell growth and division absent the proper signals
Continuous growth and division even given contrary signals
Avoidance of programmed cell death
Limitless number of cell divisions
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Promoting blood vessel construction
Invasion of tissue and formation of metastases
The progression from normal cells to cells that can form a detectable mass to outright cancer
involves multiple steps known as malignant progression.
Signs and symptoms
Metastatics cancer is cancer that spread from the place where it started to another place in the
body. The process by which cancer cells spread to other parts of the body is called metastasis.
Symptoms of cancer metastasis depend on the location of the tumor.
When cancer begins, it produces no symptoms. Signs and symptoms appear as the mass grows or
ulcerates. The findings that result depend on the cancer's type and location. Few symptoms are
specific. Many frequently occur in individuals who have other conditions. Cancer is a "great
imitator". Thus, it is common for people diagnosed with cancer to have been treated for other
diseases, which were hypothesized to be causing their symptoms.
Local symptoms
Local symptoms may occur due to the mass of the tumor or its ulceration. For example, mass
effects from lung cancer can block the bronchus resulting in cough or pneumonia; esophageal
cancer can cause narrowing of the esophagus, making it difficult or painful to swallow; and
colorectal cancer may lead to narrowing or blockages in the bowel, affecting bowel habits.
Masses in breasts or testicles may produce observable lumps. Ulceration can cause bleeding that,
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if it occurs in the lung, will lead to coughing up blood, in the bowels to anemia or rectal
bleeding, in the bladder to blood in the urine and in the uterus to vaginal bleeding. Although
localized pain may occur in advanced cancer, the initial swelling is usually painless. Some
cancers can cause a buildup of fluid within the chest or abdomen.
Systemic symptoms
General symptoms occur due to effects that are not related to direct or metastatic spread. These
may include: unintentional weight loss, fever, excessive fatigue and changes to the skin. Hodgkin
disease, leukemias and cancers of the liver or kidney can cause a persistent fever.
Some cancers may cause specific groups of systemic symptoms, termed paraneoplastic
phenomena. Examples include the appearance of myasthenia gravis in thymoma and clubbing in
lung cancer.
Metastasis
Cancer can spread from its original site by local spread, lymphatic spread to regional lymph
nodes or by haematogenous spread via the blood to distant sites, known as metastasis. When
cancer spreads by a haematogenous route, it usually spreads all over the body. The symptoms of
metastatic cancers depend on the tumor location and can include enlarged lymph nodes (which
can be felt or sometimes seen under the skin and are typically hard), enlarged liver or enlarged
spleen, which can be felt in the abdomen, pain or fracture of affected bones and neurological
symptoms.
Causes
The majority of cancers, some 90–95% of cases, are due to environmental factors. The remaining
5–10% are due to inherited genetics. Environmental, as used by cancer researchers, means any
cause that is not inherited genetically, such as lifestyle, economic and behavioral factors and not
merely pollution. Common environmental factors that contribute to cancer death include tobacco
(25–30%), diet and obesity (30–35%), infections (15–20%), radiation (both ionizing and non-
ionizing, up to 10%), stress, lack of physical activity and environmental pollutants.
It is not generally possible to prove what caused a particular cancer, because the various causes
do not have specific fingerprints. For example, if a person who uses tobacco heavily develops
lung cancer, then it was probably caused by the tobacco use, but since everyone has a small
chance of developing lung cancer as a result of air pollution or radiation, the cancer may have
developed for one of those reasons. Excepting the rare transmissions that occur with pregnancies
and occasional organ donors, cancer is generally not a transmissible disease.
Chemicals
Smoking and cancer
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The incidence of lung cancer is highly correlated with smoking.
Exposures to particular substances have been linked to specific types of cancer. These substances
are called carcinogens.
Tobacco smoke, for example, causes 90% of lung cancer. It also causes cancer in the larynx,
head, neck, stomach, bladder, kidney, esophagus and pancreas. Tobacco smoke contains over
fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons.
Tobacco is responsible about one in five cancer deaths worldwide and about one in three in the
developed world. Lung cancer death rates in the United States have mirrored smoking patterns,
with increases in smoking followed by dramatic increases in lung cancer death rates and, more
recently, decreases in smoking rates since the 1950s followed by decreases in lung cancer death
rates in men since 1990.
In Western Europe, 10% of cancers in males and 3% of cancers in females are attributed to
alcohol exposure, especially liver and digestive tract cancers. Cancer from work-related
substance exposures may cause between 2–20% of cases, causing at least 200,000 deaths.
Cancers such as lung cancer and mesothelioma can come from inhaling tobacco smoke or
asbestos fibers, or leukemia from exposure to benzene.
Diet and exercise
Diet and cancer
Diet, physical inactivity and obesity are related to up to 30–35% of cancer deaths. In the United
States excess body weight is associated with the development of many types of cancer and is a
factor in 14–20% of cancer deaths. A UK study including data on over 5 million people showed
higher body mass index to be related to at least 10 types of cancer and responsible for around
12,000 cases each year in that country. Physical inactivity is believed to contribute to cancer risk,
not only through its effect on body weight but also through negative effects on the immune
system and endocrine system. More than half of the effect from diet is due to overnutrition
(eating too much), rather than from eating too few vegetables or other healthful foods.
Some specific foods are linked to specific cancers. A high-salt diet is linked to gastric cancer.
Aflatoxin B1, a frequent food contaminant, causes liver cancer. Betel nut chewing can cause oral
cancer. National differences in dietary practices may partly explain differences in cancer
incidence. For example, gastric cancer is more common in Japan due to its high-salt diet, While
colon cancer is more common in the United States
Infection
Worldwide approximately 18% of cancer deaths are related to infectious diseases. This
proportion ranges from a high of 25% in Africa to less than 10% in the developed world. Viruses
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are the usual infectious agents that cause cancer but cancer bacteria and parasites may also play a
role.
Oncoviruses (viruses that can cause cancer) include human papillomavirus (cervical cancer),
Epstein–Barr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma), Kaposi's
sarcoma herpesvirus (Kaposi's sarcoma and primary effusion lymphomas), hepatitis B and
hepatitis C viruses (hepatocellular carcinoma) and human T-cell leukemia virus-1 (T-cell
leukemias). Bacterial infection may also increase the risk of cancer, as seen in Helicobacter
pylori-induced gastric carcinoma. Parasitic infections associated with cancer include
Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes,
Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma).
Human tumour viruses
Virus (Group) Associated Human Cancer
DNA VIRUSES
Papilloma virus family
Human papilloma virus (HPV) Genital tumours, squamous cell carcinoma
(various subtypes)
Herpes virus family
Kaposi sarcoma
Human herpes virus 8 (HHV8)
Burkitt's lymphoma, Hodgkin's disease, Nasopharyngeal
Epstein-Barr virus (EBV)
carcinoma
Hepadnavirus family
Hepatitis B virus Hepatocellular carcinoma
RNA VIRUSES
Retrovirus family
Human T-cell leukaemia virus Adult T-cell leukaemia
Human immunodeficiency AIDS-related malignancies
virus
Flavivirus family
Hepatocellular carcinoma
Hepatitis C virus
Radiation
Up to 10% of invasive cancers are related to radiation exposure, including both ionizing
radiation and non-ionizing ultraviolet radiation. Additionally, the majority of non-invasive
cancers are non-melanoma skin cancers caused by non-ionizing ultraviolet radiation, mostly
from sunlight. Sources of ionizing radiation include medical imaging and radon gas.
Ionizing radiation is not a particularly strong mutagen. Residential exposure to radon gas, for
example, has similar cancer risks as passive smoking. Radiation is a more potent source of
cancer when combined with other cancer-causing agents, such as radon plus tobacco smoke.
Radiation can cause cancer in most parts of the body, in all animals and at any age. Children and
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adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation
exposure before birth has ten times the effect.
Medical use of ionizing radiation is a small but growing source of radiation-induced cancers.
Ionizing radiation may be used to treat other cancers, but this may, in some cases, induce a
second form of cancer. It is also used in some kinds of medical imaging.
Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin
malignancies. Clear evidence establishes ultraviolet radiation, especially the non-ionizing
medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most
common forms of cancer in the world.
Non-ionizing radio frequency radiation from mobile phones, electric power transmission and
other similar sources have been described as a possible carcinogen by the World Health
Organization's International Agency for Research on Cancer. However, studies have not found a
consistent link between mobile phone radiation and cancer risk.
Heredity
The vast majority of cancers are non-hereditary ("sporadic"). Hereditary cancers are primarily
caused by an inherited genetic defect. Less than 0.3% of the population are carriers of a genetic
mutation that has a large effect on cancer risk and these cause less than 3–10% of cancer. Some
of these syndromes include: certain inherited mutations in the genes BRCA1 and BRCA2 with a
more than 75% risk of breast cancer and ovarian cancer and hereditary nonpolyposis colorectal
cancer (HNPCC or Lynch syndrome), which is present in about 3% of people with colorectal
cancer, among others.
Physical agents
Some substances cause cancer primarily through their physical, rather than chemical, effects. A
prominent example of this is prolonged exposure to asbestos, naturally occurring mineral fibers
that are a major cause of mesothelioma (cancer of the serous membrane) usually the serous
membrane surrounding the lungs. Other substances in this category, including both naturally
occurring and synthetic asbestos-like fibers, such as wollastonite, attapulgite, glass wool and
rock wool, are believed to have similar effects. Non-fibrous particulate materials that cause
cancer include powdered metallic cobalt and nickel and crystalline silica (quartz, cristobalite and
tridymite). Usually, physical carcinogens must get inside the body (such as through inhalation)
and require years of exposure to produce cancer.
Physical trauma resulting in cancer is relatively rare. Claims that breaking bones resulted in bone
cancer, for example, have not been proven. Similarly, physical trauma is not accepted as a cause
for cervical cancer, breast cancer or brain cancer. One accepted source is frequent, long-term
application of hot objects to the body. It is possible that repeated burns on the same part of the
body, such as those produced by kanger and kairo heaters (charcoal hand warmers), may produce
skin cancer, especially if carcinogenic chemicals are also present. Frequent consumption of
scalding hot tea may produce esophageal cancer. Generally, it is believed that the cancer arises,
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or a pre-existing cancer is encouraged, during the process of healing, rather than directly by the
trauma. However, repeated injuries to the same tissues might promote excessive cell
proliferation, which could then increase the odds of a cancerous mutation.
Chronic inflammation has been hypothesized to directly cause mutation. Inflammation can
contribute to proliferation, survival, angiogenesis and migration of cancer cells by influencing
the tumor microenvironment. Oncogenes build up an inflammatory pro-tumorigenic
microenvironment.
Hormones
Some hormones play a role in the development of cancer by promoting cell proliferation.
Insulin-like growth factors and their binding proteins play a key role in cancer cell proliferation,
differentiation and apoptosis, suggesting possible involvement in carcinogenesis.
Hormones are important agents in sex-related cancers, such as cancer of the breast,
endometrium, prostate, ovary and testis and also of thyroid cancer and bone cancer. For example,
the daughters of women who have breast cancer have significantly higher levels of estrogen and
progesterone than the daughters of women without breast cancer. These higher hormone levels
may explain their higher risk of breast cancer, even in the absence of a breast-cancer gene.
Similarly, men of African ancestry have significantly higher levels of testosterone than men of
European ancestry and have a correspondingly higher level of prostate cancer. Men of Asian
ancestry, with the lowest levels of testosterone-activating androstanediol glucuronide, have the
lowest levels of prostate cancer.
Other factors are relevant: obese people have higher levels of some hormones associated with
cancer and a higher rate of those cancers. Women who take hormone replacement therapy have a
higher risk of developing cancers associated with those hormones. On the other hand, people
who exercise far more than average have lower levels of these hormones and lower risk of
cancer. Osteosarcoma may be promoted by growth hormones. Some treatments and prevention
approaches leverage this cause by artificially reducing hormone levels and thus discouraging
hormone-sensitive cancers.
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