Essentials

Oncology Practise Essentials

Oncology Basics

Tutorial 1
Cancer Primer
Essentials Oncology Basics
Oncology Practise Essentials

Tutorial 1
Cancer Primer

Tutorial 1: Cancer Primer is an introduction to the basic characteristics and biology of cancer – a
group of over 200 different diseases. Key terms and tumour classifications are also defined. All this
is necessary grounding for tutorials two to five in the Oncology Basics program.

Goals and Objectives

Upon completion of this program you will be able to:

• Describe the key characteristics of cancer cells.

• Define the following key terms – neoplasms, benign tumours, malignant tumours, anaplasia,
hyperplasia, dysplasia, metastasis.
• Identify the cells of origin in the following tumour classifications – carcinoma, adenocarcinoma,
squamous cell carcinoma, sarcoma, glioma, astrocytoma.
• Describe the different phases of the cell cycle.
• Describe how tumour cell growth differs from normal cell growth.

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Definition and characteristics of cancer cells

Cancer cells are typically characterized by abnormalities in growth, division and location.

Uncontrolled Proliferation

Cells in normal tissues have constraints or feedback mechanisms to regulate growth. They
proliferate until there are enough cells to maintain the physiologic needs of the tissue or organ.
Cancer cells lack or fail to respond to normal homeostatic mechanisms that control cell division
or cell growth. The capacity for persistent, uncontrolled proliferation is the distinguishing property of
malignant cells. Without intervention, cancerous tissues grow in an unrestrained manner, leading
to tissue invasion, metastasis and ultimately death. Some cancers are composed of rapidly dividing
cells while others are composed of cells that divide more slowly than normal. This differs from the
old belief that cancer cells simply divide more rapidly than do normal cells.

Cell growth associated with carcinogenesis involves two classes of genes: 1) oncogenes, and
2) tumour suppressor genes.
• Oncogenes develop from protooncogenes, which are present in all cells and serve as regulators
of the cell cycle. Protooncogenes mutate when exposed to carcinogenic agents such as
radiation, chemicals or viruses, or as a result of inherited factors. Activation of oncogenes results
in dysregulation of normal cell growth, which produces excessive cellular proliferation.

• Tumour suppressor genes regulate and inhibit inappropriate cellular growth and proliferation.
Mutation of these genes results in loss of control over normal cell growth.

Inappropriate Ability to Invade Surrounding Tissues

Cell populations that make up body tissues normally remain segregated (i.e. one type of cells does
not invade physiologic structure belonging to a different type of cells). In contrast, malignant cells
lack the constraints that inhibit invasive growth. As a result, cells of a solid tumour can penetrate
adjacent tissues, allowing the cancer to spread.

Decreased Cellular Differentiation and other cellular changes

Most normal cells evolve through the process of differentiation, which means that they develop
from a primitive cell with few specialized properties into a cell with more specific morphology
and physiologic functions. Cancer cells have generally lost some or all of these differentiated
characteristics and cannot perform the intended physiologic functions of their tissue of origin.

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Malignant cells are also genetically unstable and lose the normal cell structure and function typical
of the cells of their origin.

Cancer cells may also show changes in the cell membrane, and exhibit different protein and
enzyme content, different shapes and appearances, and chromosomal abnormalities. Pathologists
use all of these characteristics to distinguish between malignant and benign cells, and to classify
cancers to specific tumour types. Cancer treatment, especially chemotherapy and radiotherapy,
exploits the differences in growth patterns between cancer cells and normal cells. Some drugs also
capitalize on other biochemical differences between normal and malignant cells.

Metastasis: Ability to Establish New Growth At Distant Sites

Cancer cells have a unique ability to “break away” and metastasize, or spread to distant sites of the
body. Cancer cells which break away from the original tumour mass frequently travel via the blood
or lymphatic system, establishing a new secondary tumour (metastasis) elsewhere.

Most tumour cells that detach from the primary tumour do not survive in the systemic circulation.
Survival of these tumour cells depends on three factors:

• The tumour cells or cell aggregates must receive the necessary nutrients at the distant site
• The host immune system must be overcome
• Angiogenesis (new blood vessel formation) must be initiated

Angiogenesis has been recognized as an important step in primary tumour growth and metastasis.
It has become a target for the development of new anticancer drugs.

Key Sites and Characteristics of Metastasis

Local metastases generally invade the lymphatic system. Distant metastases commonly involve the
brain, lung, bone and liver. Each cancer has a distinct pattern of metastasis (e.g. prostate cancer
commonly metastasizes to the bone, but rarely to the brain). Metastasis can occur at any time in
the growth of a cancer, and may occur before or after removal of the primary tumour. A cancer cell
that has metastasized retains many of the characteristics of the original cancer cells. For example,
a patient with breast cancer that has metastasized to the liver does NOT have liver cancer. This is
often misunderstood by the patient. The breast cancer cells are growing in the liver, and the disease
is treated with regimens against the original malignant breast tumour cells.

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Cancer terminology:
Key terms in oncology Did You Know

Neoplasms or tumours (terms used interchangeably) The word “cancer” arose

are masses of newly formed tissue characterized by new from early descriptions of
and abnormal cell development. They may be benign or malignancies in which claw-like
malignant. (Note: Neoplasm means “new growth.”) projections extended from the
central tumour. These claws
Benign tumours are generally encapsulated and slow
resembled those of a crab –
growing. They usually resemble the cells from which they
the symbol of the astrological
developed, generally do not metastasize, and rarely recur
sign of cancer.
if removed. Benign tumours are not often harmful, but can
cause harm and even death if the growth exerts pressure
or occupies space required for vital organ functioning.

Malignant or cancerous tumours are defined as

“uncontrolled growth of cells” which manifest as:

• Rapid proliferation
• Decreased cellular differentiation
• Invasion of surrounding tissues
• Ability to metastasize

A diagnosis of “malignant” versus “benign” cancer is made at

the microscopic level through pathology review. Under the
microscope, cancer cells typically show evidence of mitotic
activity and abnormal cellular structure and organization. As
a result, cancer cells cease to perform their normal functions.
The loss of structure and function is referred to as anaplasia;
this ultimately leads to death unless the process is halted.

Hyperplasia is an increase in the number of cells in

a tissue or organ. It may precede the development of
neoplasms by several months to years.

Dysplasia is an abnormal change in the size, shape or

organization of cells in a tissue. Dysplastic changes may
precede development of neoplasms by months or years.

Metastasis is the process by which malignant tumour cells

spread to distant parts of the body. Metastasis is the cause
of most cancer-related deaths.

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Classification of tumours
Benign tumours are named by adding the suffix, “-oma”, to the name of the cell type (e.g. lipoma is
a benign growth in fat tissue).

Malignant tumours are classified by their tissue of origin. It is critical to know the cancer’s tissue
of origin because each type of cancer cell responds differently to therapy and the prognosis from
different cancer cell types varies significantly.

Malignancies are classified into hematologic and solid tumours.

1) Hematologic malignancies include acute and chronic leukemias, multiple myeloma and
lymphomas.

2) Solid tumours are further classified by the cells of origin: epithelial cells (carcinomas); connective
tissues such as bone, fat, cartilage and muscle (sarcomas); neural tissues; and gonadal tissues.
• Carcinomas are subdivided into tumours that are predominantly glandular or ductal in origin
(adenocarcinomas), and those that derive from stratified squamous epithelium (squamous cell
carcinomas).
• Carcinoma in situ is a malignant cancer limited to the site of origin and has not yet invaded
the basement membrane. Carcinoma in situ is a pre-invasive stage of malignancy and can be
cured with complete surgical removal of the tumour (e.g. carcinoma in situ of the cervix).
Most carcinomas have progressed beyond this stage at the time of diagnosis.
• Neural tumours are classified based on the cells from which they arise. For example, a brain
tumour arising from a glial cell is called a glioma; a brain tumour from an astrocyte is called an
astrocytoma.

Grading and Staging of Malignant Tumours

At the time of diagnosis, the pathologist will determine the tissue type of origin, the tumour
grade and the stage of the cancer. These parameters offer important prognostic information and
will guide the selection of treatment. Different cancer types have different staging and grading
systems.

Tumour grade reflects the histology of the cancer cells. It is based on the degree of differentiation
of the tumour cells and their mitotic activity (an estimate of the tumour growth rate). The less a
tumour cell appears to resemble a normal cell and the greater the number of cells active in cell division,
the higher the grade. A higher grade generally correlates with a more aggressive tumour and a
poorer prognosis.

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The stage of a cancer signifies the extent of the disease. Most solid cancers are classified into stages
0 to IV – stage 0 indicates carcinoma in situ; stage IV indicates metastatic disease. The TNM staging
system is the most common staging system, and includes the evaluation of three variables:

• Size of the primary lesion (T)

• Involvement of regional lymph nodes (N)
• Presence of distant metastases (M)

Once treatment has begun, staging may be repeated to evaluate the effectiveness of the
treatment.

Molecular biology of cancer: Signal transduction

Protooncogenes are genes that normally code for growth factors and/or their receptors. Examples
include:

• Epidermal growth factors

• Vascular endothelial growth factors
• Epidermal growth factor receptors
• Vascular endothelial growth factor receptors

Protooncogenes can become oncogenes (genes that evoke abnormal cell growth) when they
undergo mutations or increased expression. The activation of oncogenes can potentially lead to
the development of cancer.

Signal Transduction Process

Signal transduction refers to a process whereby extracellular signaling molecules activate

a membrane receptor, eliciting an intracellular response. It often involves a number of
phosphorylation reactions within the cell. The signal alters gene expression and results in an
increased production of proteins that control cell function. For example, a growth factor will bind
to and activate its receptor, thereby eliciting an activation signal that is then conveyed to a series of
other proteins, and eventually to the nucleus.

Protein kinase enzymes (mainly tyrosine kinases) are often involved in the phosphorylation
process. These enzymes are the targets of many new anticancer treatments. Examples of tyrosine
kinase inhibitors include erlotinib and gefitinib.

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Molecular biology of cancer: The cell cycle

All cells reproduce in a multi-phase cell cycle. Increases in signal transduction can lead to increased
stimulation of cell replication and uncontrolled cell growth. Understanding how normal cells and
cancer cells grow leads to better understanding of: 1) the pharmacology of antineoplastic drugs in
the treatment of cancer; and 2) the toxicities associated with these agents. Radiotherapy and many
anticancer drugs reduce the level of uncontrolled cellular growth that is the hallmark of cancer
cells.

Phases of the Cell Cycle

As illustrated in Figure 1, the cell cycle includes four key stages: Gap1 (G1), Synthesis (S), Gap2 (G2)
and Mitosis (M). Following cell division in mitosis, cells are destined to either:

• Go back into the cell cycle at the G1 phase, or

• Enter a dormant or resting phase G0  where cells can rest, proceed to cellular differentiation, or die.
This stage is not considered part of the cell cycle as cells are not undergoing active division.
Most normal human cells exist predominantly in the differentiated G0 phase, during which
they perform the work for which they are intended (e.g. kidney cells filter urine). Because
chemotherapy mainly targets rapidly dividing cells, cancer cells in the G0 phase are not as
susceptible to the toxic effects of chemotherapy as in other cell cycle phases.

Figure 1
Cell Cycle Overview
G2
The cell “double checks” the The cell prepares for
duplicated chromosomes for
error, making any needed mitotic cell division in
repairs. Mitosis
phases G1, S, and G2.
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k Normal cells require a
S N
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G1 stimulus (cell loss, injury or
I

increased cellular function)

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duplicated by the
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excluding the chromosomes,
to induce a recruitment
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are duplicated. of cells from the resting
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Cell cycle arrest.
® Clinical Tools. Inc

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Multi-Phase Cycle, Before and

During Cell Division Figure 2
Cell Cycle Mitosis
G1 Phase Enzymes for Deoxyribonucleic acid (DNA)
synthesis are manufactured. Parent cell

S Phase In the Synthesis Phase DNA replication occurs.

The DNA coil unwinds, and an identical strand of
DNA is synthesized with the help of the enzyme Prophase
DNA polymerase. When DNA replication is
complete, new and old DNA strands coil to form
double-stranded DNA.
Metaphase
G2 Phase This is a short, pre-mitotic phase during which
Ribonucleic acid (RNA) and specialized proteins
are produced to form the mitotic spindle.

M Phase As illustrated in Figure 2, mitosis or the cell Anaphase

Early
division phase is further categorized into
four sub-phases:

Prophase
The nucleus of the cell disintegrates, releasing
chromosomes into the cytoplasm, and the Anaphase
Late
protein spindle structure is synthesized.

Metaphase
Chromosomes line up along the centre of the
cell.

Anaphase
Chromosomes separate and migrate to opposite Telophase
ends of the cell along the mitotic spindle. Cell division
Two daughter cells

Telophase
Two new nuclei are formed and cell division
takes place, producing two identical daughter
cells.

© LifeART MediClip image, 2011

Wolters Kluwer Health, Inc.- Lippincott Williams & Wilkins.
All rights reserved

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MANY Anticancer Drugs Target Rapidly Proliferating Cells

Many anticancer drugs are designed to target the cell cycle. Drugs with activity in a particular phase
of the cell cycle are called cell cycle phase-specific. For example, antimetabolites are active during the
S Phase. At any time, tumour cells can be at various phases of the cell cycle. Chemotherapy agents
that are cell cycle phase-specific should be given as a continuous infusion or in multiple repeated
fractions in order to capture as many cells that are entering into the cell cycle as possible.

In contrast, cell cycle phase-non-specific agents have activity in multiple phases of the cell cycle. The
tumour activity of these agents are dose-dependent. Cell cycle phase-non-specific agents include
alkylating agents such as cyclophosphamide and melphalan. Interestingly, some anticancer drugs
(e.g. endocrine therapy) have activities that are not related to the cell cycle events at all.

Molecular biology of cancer:

Kinetics of tumour cell growth Figure 3
Gompertzian growth curve
The study of tumour growth led to the development of
Cells
many basic principles of cancer chemotherapy. Tumour (log10) 108 cells
growth can be modeled through “Gompertzian kinetics,”
Tumour first
named after Gompertz, a German insurance agent palpable
who developed a mathematical model to describe the
Log phase of
relationship between an individual’s current age and growth – Short
expected age of death. As illustrated in Figure 3, this model MDT and High GF
also describes expected tumour cell growth.
MDT
Minimum Detection Time
“Growth Fraction” in a Tumour GF
Growth Fraction
In both normal tissue and malignant tumours, some cells
are going through the cell cycle while others are “resting”
in the G0 phase. The ratio of proliferating cells to G0 cells Reprinted with permission of the World Small
Animal Veterinary Association from Blackwood
L. How antitumour drugs work. WSAVA 2008
in a tumour mass is called the Growth Fraction (GF). In Dublin World Congress Proceedings

other words, the growth fraction signifies the percentage of

proliferating cells in a tumour mass.

Tumours with a high growth fraction are likely to be more

susceptible to chemotherapy compared to tissues with a
low growth fraction. Most chemotherapy agents directly
interfere with the synthesis and/or function of DNA during
the process of mitosis.

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Initial Tumour Growth Is Very Rapid

Early phase growth is exponential, so it is better to give chemotherapy in this phase since the growth
fraction is very high (i.e. most of the cells are dividing). Cells are very susceptible to chemotherapy in the high
growth period. As the tumour grows, the growth fraction decreases and the rate of growth starts to plateau.
At this time, there are fewer cells dividing. Slower growth in a large tumour may be due to decreased
availability of oxygen, nutrients and hormones. Also, toxic metabolites and wastes accumulate, because the
vascular supply to the large tumour cannot support growth of all the cells.

Predictive Value of the Growth Fraction

Knowing the growth fraction can help predict how a tumour will respond to chemotherapy.

• As a rule, solid tumours (e.g. breast, lung, colon and prostate) have a lower growth fraction and,
therefore, will not respond as well to chemotherapy as haemopoietic cancers (such as leukemias and
lymphomas) which have a higher growth fraction.
• Knowing the growth fraction and sensitivity to anticancer drugs can help predict which normal
tissues will be most affected by treatment.
• Tissues which are rapidly proliferating and have a high growth fraction will be most affected by
anticancer drug treatments (e.g. bone marrow, GI epithelium, hair follicles, etc.). Toxicities are
greatest in those tissues because the rapidly proliferating cells will be highly targeted by the
therapy.

Diagnosis and Treatment

Unfortunately, most cancers are diagnosed when a patient already has symptoms, or the tumour
has reached a sufficient size to be clinically detected by physical or radiological examination.

At the point of diagnosis, the cancer cell number may already be very large (e.g. one billion cells
present in a tumour of about 1 cm in diameter). Also, the Gompertzian growth curve will have
already progressed to the plateau phase, meaning a lower growth fraction and fewer cells that are
highly susceptible to chemotherapy.

Initial treatment for many cancers is aimed at decreasing tumour size, usually with surgery
(e.g. debulk tumour) or radiotherapy, which stimulates cells to reenter the cell cycle (i.e. recruitment).
The idea is to get tumour growth to shift downward on the Gompertzian growth curve so that the
growth fraction increases as cells begin dividing and the tumour cell population becomes more
sensitive to drug therapy. At this time, chemotherapy is administered.

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Molecular biology of cancer: Apoptosis

Apoptosis or “programmed cell death” is an orderly process of cell death in which the cell shrinks
away from surrounding cells and forms apoptotic bodies to degrade its nuclear DNA. This process
usually occurs without damaging surrounding cells.

A number of chemotherapy agents work by inducing DNA damage that stimulates cancer cell
apoptotic death.

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