Cancer: Etiology, Molecular Basis, and Cellular Characteristics

Defining Cancer and Tumors (Neoplasia)

In normal circumstances, the proliferation of body cells is under strict control. Cells
differentiate, divide, and die in a sequential manner in a healthy organism. Cancer is
characterized by the loss of control of cellular growth and development, leading to
excessive proliferation and spread of cells. The term "Cancer" is derived from a Latin
word meaning crab, presumed to originate from the character of cancerous cells which
can migrate, adhere, and cause pain (like a crab) to any part of the body.

Neoplasia literally means new growth. Uncontrolled growth of cells results in tumors
(a word originally used to represent swelling). Oncology (Greek: oncos—tumor) deals
with the study of tumors.

The tumors are of two main types:

1. Benign tumors: They usually grow by expansion and remain encapsulated in a

layer of connective tissue. They are normally not life-threatening (e.g., moles,
warts) and are not considered true cancers.

2. Malignant tumors or cancers: They are characterized by uncontrolled

proliferation and spread of cells to various parts of the body, a process referred
to as metastasis. Malignant tumors are invariably life-threatening (e.g., lung
cancer, leukemia).

About 100 different types of human cancers have been recognized:

• Cancers arising from epithelial cells are referred to as carcinomas.

• Cancers arising from connective tissues (like bone, muscle, fat) are known as
sarcomas.

Molecular Basis of Cancer: Oncogenes and Antioncogenes

Cancer is caused by a genetic change in a single cell, resulting in its uncontrolled

multiplication. Thus, tumors are generally monoclonal. This control involves two main
types of regulatory genes:

1. Oncogenes (Growth Promoters)

• Proto-oncogenes are normal cellular genes that code for various proteins that
control cell adhesion, growth, and division. They encode for growth-regulating
proteins.
 • If mutated or excessively activated, proto-oncogenes can become abnormally
functioning oncogenes capable of causing cancer. As many as 100 different
oncogenes have been discovered in human cancers.

• The activation of protooncogenes is an important step in carcinogenesis.

2. Antioncogenes (Tumor Suppressors)

• Also present in all cells are antioncogenes, or tumor suppressor genes (e.g.,
the p53 gene), which suppress the activation of specific oncogenes.

• The products of these genes act as "breaks" and regulate cell proliferation.

• Therefore, loss or inactivation of antioncogenes can allow activation of

oncogenes that lead to cancer (e.g., retinoblastoma, certain breast and lung
cancers).

3. Genes Regulating Apoptosis (Cell Death)

• A third category of genes controls programmed cell death (apoptosis).

• The gene bcl-2, for example, can cause B-cell lymphoma by preventing
apoptosis. Overexpression of these genes allows potentially cancerous cells to
survive long enough for other mutations to accumulate.

Etiology: Causes of Altered Genes

Cancers are generally multifactorial in origin. The probability of mutations is greatly

increased when a person is exposed to certain factors. A survey in the USA showed that
about 90% of all cancer deaths are due to avoidable factors such as tobacco,
pollution, alcohol, and diet.

1. Chemical Carcinogens

Chemical substances that can cause mutation are called carcinogens. It is estimated
that almost 80% of human cancers are caused by chemical carcinogens, which can be
organic (e.g., benzo(a)pyrene) or inorganic (e.g., arsenic, cadmium).

• Source: Occupation (asbestos, benzene), Diet (aflatoxin B), Drugs

(diethylstibesterol), and Life style (cigarette smoke).

• The carcinogens that cause the greatest number of deaths are those in cigarette
smoke, causing over 30% of all cancer deaths and at least 85% of lung cancer
deaths.

• Mechanism: Most chemical carcinogens (procarcinogens) require prior

metabolism (often by cytochrome P450) to become an ultimate carcinogen.
 These ultimate carcinogens can covalently bind to DNA, causing unrepairable
damage and mutations.

2. Radiation Energy

Ionizing radiation (x-rays, gamma rays, particle radiation) and even ultraviolet (UV)
light can predispose individuals to cancer.

• Ions formed in tissue cells are highly reactive and can rupture DNA strands,
causing mutations.

• Exposure to UV rays specifically results in the formation of pyrimidine dimers in

DNA, which are molecular damages responsible for carcinogenesis.

3. Carcinogenic Viruses (Oncoviruses)

Certain types of oncoviruses can cause various types of cancer. The involvement of
viruses in cancer etiology was first reported by Rous in 1911.

Class Members and Associated Human Cancers

Human Papilloma Virus (HPV), Hepatitis B/C virus, Epstein-Barr

DNA Viruses
virus, Kaposi Sarcoma–associated herpes virus (KSHV).

RNA Viruses
Human T-cell leukemia virus.
(Retrovirus)

• DNA Viruses: The viral DNA strand can insert itself directly into one of the host
chromosomes, causing a mutation.

• RNA Viruses: These viruses carry the enzyme reverse transcriptase that
creates a DNA copy from the viral RNA. This transcribed DNA then inserts itself
into the host cell genome.

4. Physical Irritants

Continued abrasion (e.g., by some types of food) leads to damage of tissues and rapid
mitotic replacement of cells. The more rapid the mitosis, the greater the chance for
mutation to occur.

5. Hereditary Tendency

Most cancers require two or more simultaneous mutations. In families with a

predisposition, it is presumed that one or more cancerous genes are already mutated
in the inherited genome, meaning fewer additional (somatic) mutations must take place
before cancer begins.
 Why Cancer is Still Rare

Despite trillions of new cells forming each year, only a minute fraction of cells that
mutate ever lead to cancer for several reasons:

1. Reduced Viability: Most mutated cells have less survival capability than normal
cells, and they simply die.

2. Normal Feedback Controls: Only a few mutated cells become cancerous

because most still retain normal feedback controls that prevent excessive
growth.

3. Immune System Destruction: Cells that are potentially cancerous are often
destroyed by the body’s immune system. Mutated cells form abnormal proteins
that activate the immune system to form antibodies or sensitized lymphocytes
that destroy the cells. (Immunosuppressed individuals have a much higher risk
of cancer).

4. Multiple Mutations Required: The simultaneous presence of several different

activated oncogenes is usually required to cause a cancer (e.g., one gene
promotes reproduction, another must be present to form new blood vessels).

Detailed Cellular Differences and Invasiveness

The major differences between a cancer cell and a normal cell are what make cancer
invasive and metastatic.

1. Invasiveness and Growth Limits

• Loss of Growth Factor Dependence: Cancer cells do not respect usual cellular
growth limits because they presumably do not require all the same external
growth factors necessary for normal cell growth. In fact, they often reduce their
requirement for growth factors while increasing their own production of
these factors (autocrine stimulation).

• Loss of Contact Inhibition: Normal cells form monolayers. Cancer cells lose
this inhibition and form multilayers .

• Loss of Anchorage Dependence: Cancer cells can grow without being attached
to a surface, unlike normal cells which must firmly adhere.

2. Metastasis

• Reduced Adhesion: Cancer cells are often far less adhesive to one another
than are normal cells.
 • Spread: This lack of adhesion, coupled with the loss of contact inhibition and
anchorage dependence, allows them to wander through the tissues, enter the
bloodstream, and be transported all through the body, where they form nidi
(secondary tumor sites) for numerous new cancerous growths. Metastasis is the
major cause of cancer-related morbidity and mortality.

3. Angiogenesis

• Some cancers produce angiogenic factors (e.g., Platelet-derived growth factor,

or PDGF) that cause many new blood vessels to grow into the cancer. This
supplies the copious nutrients required for rapid, indefinite tumor growth.

4. Biochemical Changes (Aerobic Glycolysis and Fetal Proteins)

• Increased Glycolysis (Warburg Effect): Fast-growing tumor cells are

characterized by a significant elevation in aerobic and anaerobic glycolysis
(the conversion of glucose to lactate, even in the presence of oxygen) to meet the
increased energy demands of rapidly multiplying cells.

• Synthesis of Fetal Proteins: Tumor cells may re-activate genes that were only
active during fetal life, leading to the synthesis of specific proteins (e.g.,
Carcinoembryonic Antigen (CEA), Alpha-fetoprotein (AFP)).

Why Do Cancer Cells Kill?

Cancer tissue competes intensely with normal tissues for nutrients.

• Because cancer cells continue to proliferate indefinitely, their numbers multiply

every day, and they soon demand essentially all the nutrition available to the
body or to an essential part of the body. As a result, normal tissues gradually
sustain nutritive death.

• Some cancers cause disruption of vital organ functions. For example, a lung
cancer might replace healthy lung tissue to the extent that the lungs cannot
absorb enough oxygen, leading to system-wide failure.

Tumor Markers

Tumor markers are biochemical indicators (abnormally produced molecules like

antigens, proteins, enzymes, and hormones) that can be measured in serum or plasma
to detect the presence of cancers.
 Chemical
Tumor Marker Associated Cancer(s) Clinical Use
Nature

Cancers of colon, Monitoring response

Carcinoembryonic
Glycoprotein stomach, lung, to therapy and
Antigen (CEA)
pancreas, and breast. detecting recurrence.

Cancers of liver
Monitoring tumor
Alpha-Fetoprotein (hepatocellular
Glycoprotein therapy and
(AFP) carcinoma) and germ
recurrence.
cells of testis.

Screening and
Cancer Antigen-125
Antigen Ovarian cancer. monitoring ovarian
(CA-125)
cancer.

Diagnosis,
Prostate Specific monitoring, and
Protein Prostate cancer.
Antigen (PSA) recurrence detection
for prostate cancer.

Cancer Therapy

Chemotherapy, employing specific anticancer drugs, is widely used.

• The effectiveness of anticancer drugs is inversely proportional to the size of

the tumor.

• The major limitation is that the drugs affect all rapidly dividing normal cells
(e.g., hematopoietic system, gastrointestinal tract, hair follicles), leading to toxic
manifestations.

• Tumor Lysis Syndrome (TLS) represents the metabolic consequences that

occur during cancer treatment, including increased uric acid and hyperkalemia.