Module 2

What is cancer?
Cancers are a group of diseases associated with abnormal growth of cells.Without any check, the
disease may keep on progressing ultimately leading to pre-mature death

Cancer refers to unregulated and unrestricted * proliferation of cells. Clinically it is seen in the
form of a growth.
Neoplasm is an abnormal mass of tissue growing in an uncoordinated way and persisting even
when the stimuli responsible for growth has been removed. A tumor is said to be benign when its
characteristics are considered relatively harmless

Malignant tumors are collectively referred to as cancers, derived from the Latin word for crab,
because they involve the tissues in a manner similar to a crab. Malignant tumor can invade and
destroy adjacent structures and spread to distant site

● Proliferation - rapid growth of cells.

● Mutation - genetic change in nucleotide sequence
● Carcinogens - cancer causing agents

What are the common cancers of human body?

Worldwide, the commonest cancers amongst men are lung, prostate, colo-rectum, stomach, and
liver cancer.Among women the most common sites diagnosed are breast, colo-rectum, lung,
cervix, and stomach cancer.

In India, amongst males common cancers in decreasing frequency are oral, lung, stomach and
colo-rectal cancers. In females, breast, cervix, colo-rectal, ovary and oral cancers are the
commonest cancers in decreasing frequency.

The incidence of these cancers varies according to the geographical area, prevalent social
customs and the socio-economic strata. For example, oral cancers are common in Indian
sub-continent and not that common in western countries. This is because of higher consumption
of chewable forms of tobacco in the form of gutkha, paan, paan masala, khaini, supari etc.
What are the common cancers of human body?
Worldwide, the commonest cancers amongst men are lung, prostate, colo-rectum, stomach, and
liver cancer.
Among women the most common sites diagnosed are breast, colo-rectum, lung, cervix, and
stomach cancer.
In India, amongst males common cancers in decreasing frequency are oral, lung, stomach and
colo-rectal cancers. In females, breast, cervix, colo-rectal, ovary and oral cancers are the
commonest cancers in decreasing frequency.
Cancer may present in a variety of ways. Ten common signs of cancers are:
● New lumps or growths or swelling
● Sore or bruise that does not heal
● A mole that changes in shape, size or color or bleed
● Persistent cough or hoarseness that last;
● Indigestion or difficulty in swallowing;
● A Change in bowel or bladder habits;
● Shortness of breath
● .Loss of appetite;
● Unexplained weight loss or tiredness; and
● Blood in urine, bowel motions or sputum

Common types of cancer:

● Carcinoma - cancer that begins in the skin or in tissues that line or cover internal organs.
There are a number of subtypes of carcinoma: adenocarcinoma - cancer that begins in the
skin or in tissues that line or cover internal organs. There are a number of subtypes of
carcinoma: adenocarcinoma, basal cell carcinoma, squamous cell carcinoma,transitional
cell carcinoma.
 ● Sarcoma - cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other
connective or supportive tissue.
● Leukemia - cancer that starts in blood-forming tissue such as the bone marrow and causes
large numbers of abnormal blood cells to be produced and enter the blood.
● Lymphoma and myeloma - cancers that begin in the cells of the immune system.
● Central nervous system cancers - cancers that begin in the tissues of the brain and spinal
cord.

What are the common causes of cancers?

Common causes of cancer are and are as follows:
1. Tobacco:
Tobacco consumption is the single most important avoidable risk factor for cancer mortality
worldwide. According to WHO, it causes an estimated 22% of cancer deaths per year. Majority
of the lung cancers are associated with smoking. Passive smoking has also been associated with
cancers in non-smoking adults. Risk increases with increasing quantity of smoking. In Indian
subcontinent use of smokeless tobacco is more prevalent. These include use of gutkha, pan
masala, masheri, raw tobacco, betel quid etc. Tobacco is associated with cancers of lung, oral
cavity, throat, oesophagus, urinary bladder, pancreas, kidney, liver, stomach, bowel, cervix,
ovary, nose and sinus as well as some types of leukemia Various Studies have shown that those
who quit tobacco have a better survival than those who don't.
A new trend is that of the use of e-cigarettes.They are battery operated LED light containing
devices which light up when used and release nicotine.

2. Alcohol :
Alcohol itself is associated with several cancers, the risk of whicH increases with increasing
quantity of alcohol consumed. It has synergistic action along with smoking and if a person
consumes both alcohol and tobacco then the risk of developing cancer is much higher than the
risk associated with consuming them independently. Alcohol use is a risk factor for many cancer
types including cancer of the oral cavity, pharynx, larynx, esophagus, liver, colo-rectum and
breast

3. Areca Nut :
It is also called supari in India. It may be chewed alone or in combination with betel leaf, catechu
and slaked lime – called as Pan or betel quid. Powdered areca nut in ready to eat mixtures with
other ingredients is called Pan Masala. If tobacco is added to these then it is called Gutkha. It is
associated with Sub Mucous Fibrosis which is a precancerous condition where the mouth
opening of the chewer decreases gradually. It has been included as a group I carcinogen byThe
International Agency for Research into Cancer(IARC). Its use has been found to lead to oral
cancer. Chemicals like arsenic cause contamination of drinking water and can result in lung
cancers. Household air is polluted by coal fires and causes lung cancer.

3. Lifestyle factors :
These include unhealthy eating habits and lack of physical activity. High body mass index is
associated with cancers of esophagus, colorectum, breast, endometrium etc. Excessive
consumption of red meat is associated with colorectal cancers. Healthy diets, including
vegetables, salads and fruits have been found to decrease risk of developing certain cancers.

4. Obesity:
It refers to excessive fat accumulation. If body mass index (BMI) is above 25 the person is
called overweight. Those having BMI over 30 are called obese. It is associated with increased
risk of heart diseases, diabetes and cancer like those of endometrium, colon, breast, esophagus,
pancreas etc. Besides increasing the risk of developing such cancers, obesity is also associated
with increased chances of deaths due to such cancers. Proper healthy diet and regular exercise
are required to curb the menace of obesity.
5. Occupational exposure :
Several cancers are seen to have higher association with specific occupations. Substances like
asbestos, cadmium, ethylene oxide, benzopyrene, silica, ionizing radiation including radon,
tanning devices, aluminum and coal production, iron and steel founding, have been found to be
associated with various cancers. Common cancers associated with occupational exposure include
lung, bladder, leukemia, skin etc

6. UV rays :
Ultraviolet radiation is associated with skin cancers like basal cell carcinoma, squamous cell
carcinoma and * melanoma . Exposure to ionizing radiation has been associated with increased
risk of several cancers. This has been extensively studied in survivors of atomic bomb in Japan.

7. Biological agents :
These include various viruses, parasites and bacterial infections which predispose the patient to
develop certain cancers. Human papilloma virus (HPV) is associated with cervical cancers and
oropharyngeal cancers. Hepatitis B and C are associated with liver cancers. pylori infection may
results in stomach cancer.

8. Dietary Factors
A significant proportion of cancer deaths can be attributed at least partially to dietary factors.
Diets with excessive calories from saturated fat are known to increase the risk of
hormonedependent cancers such as breast, ovarian, and endometrial cancers in females and
prostate cancer in males. In contrast, a low-fiber diet is associated with an increased risk of
colorectal cancer, whereas high dietary intake of red meat has been strongly associated an
increased risk

9. Genetic Susceptibility
There are a number of well-defined cancer syndromes, including Li-Fraumeni, hereditary
nonpolyposis colon cancer, and polyposis colon cancer syndromes, mutations in the Brca-1 and
Brca-2 oncogenes, and others. In the case of breast cancer, however, only approximately 10% of
patients have an identifiable germline mutation. Many of the inherited cancer predisposition
syndromes such as Brca-1 and 2 involve defects in DNA repair pathways

10. Immune Evasion

It has been well established for several decades that patients with compromised immunity have
an increased susceptibility to cancer. This is particularly evident in patients with acquired
immunodeficiency syndrome (AIDS), before the advent of highly active antiretroviral therapy
(HAART)

CANCER BIOLOGY:

Carcinogenesis
Carcinogenesis is the development of cancer by transforming healthy cells into cancer cells. This
complex process occurs because of mutations in DNA that prevent the normal process of
cell division. Normal cells have programmed cell death but cancer cells proliferate without
regulation. The genetic changes that cause cancer may occur in reproductive cells of the ova and
sperm and propagate to progeny. Somatic changes are acquired during an individual’s lifetim
because of exposure to carcinogenic chemicals, tobacco, radiation , and other factors. Mutations
in oncogenes that promote cell growth and tumor suppressor Genes that reduce cell growth are
important mechanisms in the dysregulation of cell division and lead to cancer.

The process of carcinogenesis may be divided into at least three stages: initiation, promotion, and
progression.
● The first stage of carcinogenesis, initiation, results from an irreversible genetic alteration,
most likely one or more simple mutations, transversions,transitions, and/or small deletions in
DNA.
● The reversible stage of promotion does not involve changes in the structure of DNA but
rather in the expression of the genome mediated through promoter-receptor interactions.
● The final irreversible stage of progression is characterized by karyotypic instablity and
malignant growth.
Cancer staging
Based on the size or extent of the primary (main) tumor and whether it has spread to other areas
of the body.
Summary staging (in situ, local, regional, and distant) is used for descriptive and statistical
analysis of tumor registry data.

Cancer cells are present only in the layer of cells where they developed and have not spread, the
stage is in situ.

If penetrated beyond the original layer of tissue, the cancer is invasive and categorized as local,
regional, or distant stage based on the extent of
spread

TNM staging
Assesses tumors in three ways:
● extent of the primary tumor (T)
● Absence or presence of regional lymph node involvement (N)
● Absence or presence of distant metastases (M).

Once the T, N, and M categories are determined, a stage of 0, I, II, III, or IV is assigned,
● stage 0 - in situ,
● stage I - early
● stage IV - the most advanced disease.
Some cancers have alternative staging systems (e.g.,leukemia).
Hallmarks of Cancer Cell
Hanahan and Weinberg (2000) listed the seven attributes of cancer
1) Self sufficiency in growth signals,
2) Insensitivity to anti-growth signals,
3) Evading apoptosis, 4)
Limitless replicative potential, telomerase and telomeres
5) Sustained angiogenesis,
6) Tissue invasion and metastasis, and
7) Genome instability. All seven attributes have received great attention in the past decade.
Growth and anti-growth signaling are really complex .
Information on cancer cell death and provocation by drugs and irradiation now requires all cell
death types to be considered apoptosis, necrosis, autophagy

Origin of Cancer Cells –The Cancer Stem Cell Model

The traditional model of cancers envisaged a “normal cell” transformed to “atypical or
dysplastic“ cell with progression into invasive or malignant cell.

This is the model that only assumes stochastic generation of cells capable of the behavior of
metastasis and progression and cellular heterogeneity of cancers. The stochastic model is used to
explain heterogeneity in cancers such as in prostate cancer

The stochastic model has to account for local recurrence and metastasis after long post-treatment
intervals. Cell of origin models cannot exclude all interactions between cancer cells and any
influence from the stroma .

Onset of cancers depend on the first two mutations and early-onset and late-onset cancer initiate.

Cancer initiation via DNA damage response and repair, induction of senescence and the
generation of driver mutations can be accommodated in stochastic and cancer stem cell models.
Driver mutations in cancer initiation are suggested to accumulate over time

The cancer stem cell model has been used to explain cancer cell origin, initiation, progression
and metastasis). Cancer stem cells as origin of cancers has attributes of hierarchical organization,
may be under-estimated and assumed to be a minor population. As in their resident or embryonic
stem cell counterparts, there are known regulators, such as p53 and WNT signaling pathways.
Cancer stem cells show c-Myc transcription profile, similar to embryonic stem cells described in
breast cancers are now described in liver, ovarian, prostate, head and neck, colon and brain
cancers, melanomas
The cancer stem cells have their specific microenvironments to allow for their specific functions;
epigenetic modifications may make cancer stem cells not reliant on its specific niche.

The functional attributes of cancer stem cells such as (i) evasion of cell death, i.e apoptosis, (ii)
telomere activation, (iii) colony formation, tumor initiation and differentiation are suited to their
role in human cancer

The lineage/clonal evolution model is used in morphological classification of cancer. One cell
type gives rise to one cancer type.

Cancer Metastases and Cancer Stem Cell Model

Cancer metastasis occurs either through progressive acquisition of metastatic potential or the
traits are acquired early during cancer initiation; this implies that metastases occurs early or late
in cancer
The acquired traits include survival and evasion of cell death, dormancy, migration, immune
escape, and ability to seed, home on targets.

Breast cancer cells reaching the bone marrow share stem cell features and markers CD24 and
CD44 as determined by double immunohistochemistry in bone marrow; these stem-like cells
ranged from 33-100% in metastases (65). CD26+CD24+ positive cancer cells found in colon
cancers, not initiating CD133+CD26+CD44 positive cells, define occurrence of metastases
Personalized Genomic Medicine and Cancer Classification
Personalized medicine, as envisioned will require individual cancer genomics and proteomics for
maximum benefit of targeted treatment for the individual; the implications of genomic cancer
medicine should encourage use of integrated cancer classification models.
Integrated Model of Cancer Classification
The model envisaged takes into account all elements of cancer. An added feature is that the
functions of proteins and signaling pathways can be derived from gene expression and
proteomics.
This means that altered or dysfunctional pathways can be supported by adding cytogenetic or
CNV data.

Recent prostate cancer survival and post-surgical recurrence used modeling based on some
aspects of the integrated classification model including mutation patterns, CNVs, targeted
signaling pathway deregulation, miRNA and cDNA profiling; new oncogenes, and CNV-based
disease risk profiles over above morphology grades were found

1) Proteomics: Normal and cancer tissues can be used for comparative proteomics. The methods
available are mass spectrometry, protein and antibody microarray and tissue microarray. In mass
spectrometry, tissue and cell protein content is quantitatively determined by analyzing peptide
content and via bioinformatics

2) cDNA Profiling and Transcriptomics; cDNA microarray profiling is the most common high
throughput method for determining expression levels of mRNA in cells and tissues

3). Copy Number variatiopn (CNV): Normal and cancer cells show variations in genes. The most
common variation is single nucleotide polymorphisms (SNPs). Variations greater than 1kilobase
of DNA is called CNV

4) Methylation status: Gene promoter methylation at the cytosine-guanine sites (CpG islands)
leads to gene transcription suppression. Demethylation leads to transcript activation. Methylation
status of cancer genes adds complexity to interpretation of gene profiling

5) miRNA Profiling: microRNAs (18-24 nucleotides) are present in plants and animals. miRNAs
play significant roles in normal development, cellular responses and in human cancer

6) Gene Sequencing: Human genome sequencing ushered in the grand promise of genomics
medicine in 2000. Now individual genes and chromosomes, and gene fusions are sequenced.
This enables direct analysis of mutations within the gene components of interest

7) Cancer Grading: Cancer grading to reflect the extent of differentiation is done for many
cancers. Grading systems vary and depend on cancer type. Morphologic attributes are used to
grade prostate cancer . Cancer grades will form an integral part of the model
How Is Cancer Diagnosed?
(“7 warning signs”)

Symptomatic
Cough, Rectal bleeding, Palpation of breast lump,Weight loss Skin abnormality- change in a
freckle or mole, red areas, Coughing up blood/chest pain Change in bowel habits, Abdominal
pain, Blood in urine, Difficulty swallowing,Hoarseness

Asymptomatic
Blood test
Screening study(ies) –colonoscopy, mammogram, total-body CT scan, MRI
Asymptomatic pick up on physical exam Leads to radiographic or surgical biopsy and then to
Pathology
Breast cancer : Screening for breast cancer is done with mammography. Mammography refers to
taking an x-ray image of the breast. Its efficacy as a screening test has been proven in several
studies
Cervical cancer : Pap smear is used to screen women for cervical cancer (Figure 7). In this a
smear taken from the cervix is evaluated under microscope to look for pre-cancerous or cancer
cells.
Oral cancers : Screening for oral cavity cancers is relevant because of easy accessibility of oral
mucosa for visual inspection without requiring any special equipment or expertise and the fact
that most of the oral carcinomas are preceded by visible pre-cancerous lesions

Pathologic assessment–Along-with clinical * evaluation, a small part of the lesion is biopsied

and * sent for histopathological examination. If required * aspiration from the lesion is sent for
cytological examination
surgery–Surgical excision with reference to cancer refers to excision of the lesion with wide
margins. Along with the primary lesion, regional lymph nodes are also addressed