Introduction Etiology of cancer Genetic and molecular basis of cancer The cell cycle Pathology of cancer Tumor origin Tumor characteristics Invasion and metastasis Diagnosis and staging Screening Diagnosis Staging and workup

1. Basic principles of
Cancer Therapy

2. Contents
Introduction
Etiology of cancer
• Genetic and molecular basis of cancer
The cell cycle
Pathology of cancer
• Tumor origin
• Tumor characteristics
• Invasion and metastasis
Diagnosis and staging
• Screening
• Diagnosis
• Staging and workup

3. Introduction
• Cancer is a group of more than 100 different diseases that are characterized
by uncontrolled cellular growth, local tissue invasion, and distant metastases.
Epidemiology
• It is now the leading cause of mortality in Americans younger than age 85
years.
• About 1.4 million cases of cancer will be diagnosed in 2007, and cancer will
claim an estimated 559,650 lives in the United States.
• The four most common cancers are prostate, breast, lung, and colorectal
cancer.
• The most common cause of cancer-related deaths in the United States is lung
cancer, which accounts for about 160,000 deaths each year.

4. ETIOLOGY OF CANCER
CARCINOGENESIS
The mechanisms by which cancers occur are incompletely understood. A cancer, or neoplasm, is thought to develop from a cell in which
the normal mechanisms for control of growth and proliferation are altered.
Current evidence supports the concept of carcinogenesis as a multistage process that is genetically regulated.
The first step in this process is initiation, which requires exposure of normal cells to carcinogenic substances.
• These carcinogens produce genetic damage that, if not repaired, results in irreversible cellular mutations.
• This mutated cell has an altered response to its environment and a selective growth advantage, giving it the potential to develop into a clonal population of neoplastic
cells.
During the second phase, known as promotion, carcinogens or other factors alter the environment to favor growth of the mutated cell
population over normal cells.
• The primary difference between initiation and promotion is that promotion is a reversible process.
• Because it is reversible, the promotion phase may be the target of future chemoprevention strategies, including changes in lifestyle and diet.
• At some point, however, the mutated cell becomes cancerous (conversion or transformation).
• Depending on the type of cancer, 5 to 20 years may elapse between the carcinogenic phases and the development of a clinically detectable cancer.
The final stage of neoplastic growth, called progression, involves further genetic changes leading to increased cell proliferation.
• The critical elements of this phase include tumor invasion into local tissues and the development of metastases.

5. Substances that may act as carcinogens or initiators include
•Chemical agents
•Physical agents
•Biologic agents.
Chemical agents
•Exposure to chemicals may occur by virtue of occupational and environmental means, as well as lifestyle habits.
•The association of aniline dye exposure and bladder cancer is one such example.
•Benzene is known to cause leukemia.
•Some drugs and hormones used for therapeutic purposes are also classified as carcinogenic chemicals).
Physical agents
•Physical agents that act as carcinogens include ionizing radiation and ultraviolet light.
•These types of radiation induce mutations by forming free radical that damage DNA and other cellular
components.
Biologic agents
•Viruses are biologic agents that are associated with certain cancers.
•The Epstein-Barr virus is believed to be an important factor in the initiation of Burkitt’s lymphoma.
•Infection with human papilloma virus is known to be a major cause of cervical cancer.
All the previously mentioned carcinogens, as well as age, gender, diet, growth factors, and
chronic irritation, are among the factors considered to be promoters of carcinogenesis.

6. GENETIC AND MOLECULAR BASIS OF CANCER
In recent years there has been marked progress in our understanding of the genetic changes that lead to the
development of cancer, largely because of improvements in research techniques and new information
generated as part of the Human Genome Project.
Two major classes of genes are involved in carcinogenesis:
• Oncogenes
• Tumor suppressor genes.
Oncogenes
• Oncogenes develop from normal genes, called protooncogenes, and may have important roles in all phases of
carcinogenesis.
• Protooncogenes are present in all cells and are essential regulators of normal cellular functions, including the
cell cycle.
• Genetic alteration of the protooncogene through point mutation, chromosomal rearrangement, or gene
amplification activates the oncogene.
• These genetic alterations may be caused by carcinogenic agents such as radiation, chemicals, or viruses
(somatic mutations), or they may be inherited (germ-line mutations).
• Once activated, the oncogene produces either excessive amounts of the normal gene product or an abnormal
gene product.
• The result is dysregulation of normal cell growth and proliferation, which imparts a distinct growth advantage to
the cell and increases the probability of neoplastic transformation.

7. • The human epidermal growth factor
receptor (HER) family of oncogenes.
• This family of receptor tyrosine kinases
contains four members: ErbB-1, also known as
epidermal growth factor receptor (EGFR), HER-
2, HER-3, and HER-4.
• When activated, these receptors mediate cell
proliferation and differentiation of cells
through activation of intracellular tyrosine
kinase receptors and downstream signaling
pathways.
• As an oncogene, the gene product is
overexpressed or amplified, resulting in
excessive cellular proliferation, metastasis,
angiogenesis, and cell survival in several
cancers.

8. Tumor suppressor genes
• In contrast, tumor suppressor genes regulate and inhibit inappropriate cellular growth and
proliferation.
• Gene loss or mutation results in loss of control over normal cell growth. Two common examples
of tumor suppressor genes are the retinoblastoma and p53 genes.
• Mutation of p53 is one of the most common genetic changes associated with cancer and is
estimated to occur in half of all malignancies.
• The normal gene product of p53 is responsible for negative regulation of the cell cycle, allowing
the cell cycle to halt for repairs, corrections, and responses to other external signals.
• Inactivation of p53 removes this checkpoint, allowing mutations to occur.
• Mutation of p53 is linked to a variety of malignancies, including brain tumors (astrocytoma);
carcinomas of the breast, colon, lung, cervix, and anus; and osteosarcoma.
• Another important function of p53 may be modulation of cytotoxic drug effects.
• Loss of p53 is associated with antineoplastic drug resistance.

9. • Another group of genes important in carcinogenesis are the DNA repair genes.
• The normal function of these genes is to repair DNA that is damaged by environmental
factors, or errors in DNA that occur during replication.
• If not corrected, these errors can result in mutations that activate oncogenes or
inactivate tumor suppressor genes.
• As more mutations in the genome occur, the risk for malignant transformation increases.
• The DNA repair genes have been classified as tumor suppressor genes because a loss in
their function results in increased risk for carcinogenesis.
• Deficiencies in DNA repair genes have been discovered in familial colon cancer
(hereditary nonpolyposis colon cancer) and breast cancer syndromes.

10. • Oncogenes and tumor suppressor genes provide the stimulatory and inhibitory signals
that ultimately regulate the cell cycle.
• These signals converge on a molecular system in the nucleus known as the cell-cycle
clock.
• The function of the clock in normal tissue is to integrate the signal input and to
determine if the cell cycle should proceed.
• The clock is composed of a series of interacting proteins, the most important of which
are cyclins and cyclin dependent kinases.
• Cyclins (especially cyclin D1) and cyclin-dependent kinases promote entry into the cell
cycle and are overexpressed in several cancers, including breast cancer.
• Cyclin-dependent kinase inhibitors have been identified as important negative regulators
of the cell cycle.

11. • When the normal regulatory mechanisms for cellular growth fail, backup defense
systems may be activated.
• The secondary defenses include apoptosis (programmed cell death or suicide) and
cellular senescence (ageing).
• Apoptosis is a normal mechanism of cell death required for tissue homeostasis.
• This process is regulated by oncogenes and tumor suppressor genes and is also a
mechanism of cellular death after exposure to cytotoxic agents.
• Overexpression of oncogenes responsible for apoptosis may produce an “immortal” cell,
which has increased potential for malignancy. The bcl-2 oncogene is an example.
• The most common chromosomal abnormality found in lymphoid malignancies is the
t(14;18) translocation.

12. • Studies show that p53 is also a regulator of apoptosis.
• Loss of p53 disrupts normal apoptotic pathways, imparting a survival
advantage to the cell.
• Recent evidence also has revealed an important role for apoptosis as a
mechanism of inherent resistance to chemotherapy.
• Cellular senescence is another important defense mechanism.
• Laboratory studies demonstrate that once a cell population has undergone a
preset number of doublings, growth stops, and cells die.
• This is known as senescence, a process that is regulated by telomeres.
• Telomeres are the DNA segments or caps at the ends of chromosomes.
• They are responsible for protecting the end of the DNA from damage.
• With each replication, the length of the telomeres is shortened.

13. • After the telomeres are shortened to a critical length, senescence is triggered.
• In this way, telomeres limit the number of cell doublings.
• In cancer cells, the function of telomeres is overcome by overexpression of an
enzyme known as telomerase.
• Telomerase replaces the portion of the telomeres that is lost with each cell division,
thereby avoiding senescence and permitting an infinite number of cell doublings.
• Telomerase is a target for antineoplastic drug development.
• As information regarding the role of oncogenes and tumor suppressor genes
accumulated, it became evident that a single mutation is probably insufficient to
initiate cancer.
• Scientists postulate that combinations of mutations are required for carcinogenesis
and that each mutation is inherited by the next generation of cells.
• Thus, several detectable genetic mutations may be present in an established tumor.

14. • Early mutations are found in both premalignant lesions and in established tumors,
whereas later mutations are found only in the established tumor.
• This theory of sequential genetic mutations resulting in cancer has been
demonstrated in colon cancer.
• In colon cancer, the initial genetic mutation is believed to be loss of the
adenomatous polyposis coli gene, which results in formation of a small benign
polyp.
• Oncogenic mutation of the ras gene is often the next step, leading to enlargement of
the polyp.
• Loss of function of DNA mismatch repair enzymes may occur at many points in the
progression of malignant transformation.
• Loss of the p53 gene and another gene, believed to be the "deleted in colorectal
cancer" gene, complete the transformation into a malignant lesion.
• Loss of p53 is thought to be a late event in the development and progression of the
malignancy.

15. • Identification of genes and other proteins involved in carcinogenesis has
several important clinical implications.
• They may be used in cancer screening to identify individuals at
increased risk for cancer and are being used to design new anticancer
agents and pies, several of which have recently been approved for use.
• Specific genetic abnormalities are so commonly associated with some
types of cancers that the presence of that abnormality aids in the
diagnosis of that cancer.
• If the presence of these genes (i.e., gene expression profile) can reliably
predict the clinical course of a cancer or response to certain cancer
therapies, then genetic analysis may also become an important
prognostic and treatment decision tool.
• An example of this is overexpression of HER-2 predicting response to
trastuzumab.

16. The cell cycle
• A proper understanding of cell cycle is essential for rational use of anticancer
drugs.
• The cells reproduce themselves through cell division.
• The first kind of cell division-the somatic cell division-involves nuclear division
(by mitosis) and cytoplasmic division (by cytokinesis).
• The whole process ensures that each daughter cell gets the same number and
kind of chromosomes as the original parent cell.
• The second type of cell division is called reproductive cell division, by which
sperm and egg cells are produced.
• This division involves a nuclear division (with cells containing haploid (n)
number of chromosomes) called meiosis followed by a cytoplasmic division
called cytokinesis.

17. • When we discuss cell cycle, particularly in relation to cancer, we restrict
our discussion to somatic cell (body cell) division because in majority of
cancers, the cell division takes place by mitosis (leaving aside few germ
cell tumours where cell division is by meiosis).
• Human cells, except for gametes, contain 23 pairs of chromosomes.
When a cell reproduces, it must produce duplicates of all its
chromosomes so that its hereditary traits may be passed on to its
successive generations.

18. Cell Cycle Phases
• G0 Phase
• Most cells do not divide constantly and spend a varying
amount of time in quiescent (calm) state outside the cell
cycle. This phase is termed as G0 (G zero).
• Neurons, skeletal muscle and cardiac muscle cells
increase in bulk through hypertrophy and spend their life
time in G0 state.
• On the contrary, bone marrow cells, GIT cells and skin
cells divide constantly.
• The growth factor action (or other stimulus such as
wound) provides momentum for the start of cell cycle
• Growth factors stimulate the production of positive as
well as negative regulators of cell cycle through signal
transduction.
• The cell cycle, in itself, consists of two major activities:
the interphase (G1 →S →G₂ phase) and the cell division
(mitosis, i.e., M-phase and cytokinesis)...

19. • Interphase
• When the cell is in-between one mitosis and the next,
it is said to be in interphase. It is during interphase that
the replication of chromosomes, occurs.
• Also the DNA, the RNAs and the proteins, needed to
produce structures that are required for doubling all
cellular components (before mitosis), are
manufactured.
• Interphase consists of three distinct phases: G₁, S and
G2 phase.
• G₁ phase is a growth (or gap) phase during which
cells are engaged in metabolism and production
of substances required for forthcoming cell
division and growth.
• In S (synthesis) phase, DNA and chromosomes
are replicated.
• S-phase is followed by another growth phase, G2
phase (or a gap period between S phase and
mitosis) where the cell prepares itself for mitotic
division into two daughter cells.
• In G₁ and G2 phase there are no events related to
chromosomal or DNA replication. These phases
simply serve as preparatory ground or gaps in
DNA synthesis.

20. • Cells that are destined to never divide again (e.g., nerve
cells, skeletal muscle cells) are permanently arrested in G₁
phase; but once a cell enters in the S-phase, it is bound to
go through the a mitosis (M-phase).
• An entry of the cell into the S-phase or M-phase is
controlled at two check points in the cell cycle one at the
start of S- and the other at the start of M-phase.
• In the quiescent G0 cells the Rb protein is not
phosphorylated.
• The unphosphorylated Rb protein serves as a brake,
keeping the cells in G₁ by inhibiting the genes essential
for passing into S-phase. In mid G₁, the cyclin-cdk C
complex phosphorylates the Rb protein to release this
brake (check point 1).
• If there is DNA damage, the tumor suppressor gene p53
stops the cycle at check point 1, allowing the
physiological repair.
• If repair fails apoptosis is initiated. Once check point 1 is
cleared the process cannot be reversed and the cell is
committed to enter into S-phase.
• Any abnormal DNA synthesis or DNA damage in S-phase
or G₁-phase can further stop the cell cycle at check point-
2 by inhibiting the formation of cyclin B-cdk 1 complex.

21. Mitosis (M-Phase) or Nuclear Division:
• Though a continuous phase, it can precisely be divided further into four
stages.
1. Prophase (Pro= before)
• Till now, the chromosomes (though duplicated) are still in a form
of tangled mass filled inside the nucleus.
• In prophase they condense into visible chromosomes (i.e., two
sister chromatids joined at centromere).
• Nuclear membrane now disintegrates and condensed
chromosomes are released into cytoplasm.
2. Metaphase (Meta = after)
• In this second stage of mitosis, the centromeres of the chromatid
pair (collectively a chromosome and its copy) line up at the exact
center of the mitotic spindle in an equatorial plane.
3. Anaphase (Ana = upward)
• In this third stage of mitosis, centromeres divide and identical sets
of chromosomes move to the opposite poles of the cell. The
separated sister chromatids are referred to as daughter
chromosomes.
4. Telophase (Telo = end)
• This end stage of mitosis is essentially the oppo site of prophase.
• During telophase, the identical sets of chromosomes at opposite
poles of the cell uncoil and revert to their thread-like chromatin
form.
• A new nuclear envelope is re-formed around chromatin mass.
Nucleoli reappear and spindle disappears.

22. Pathology of cancer
• Tumor origin
• Tumors may arise from any of four basic
tissue types: epithelial tissue, connective
tissue (i.e., muscle, bone, and cartilage),
lymphoid tissue, and nerve tissue.
• Although some malignant cells are atypical
of their cells of origin, the involved cells
usually retain enough of their parent's
traits to identify their origin.
• Benign tumors are named by adding the
suffix -oma to the name of the cell type.
• Hence, adenomas are benign growths of
glandular origin, or growths that exhibit a
glandular pattern.

23. • Some cancers are preceded by cellular changes that are abnormal, but not yet
malignant.
• Correction of these early changes could potentially prevent the occurrence of a cancer.
• Precancerous lesions may be described as consisting of either hyperplastic or
dysplastic cells.
• Hyperplasia is an increase in the number of cells in a particular tissue or organ, which
results in an increased size of the organ.
• It should not be confused with hypertrophy, which is an increase in the size of the
individual cells.
• Hyperplasia occurs in response to a stimulus and reverses when the stimulus is
removed.
• Dysplasia is defined as an abnormal change in the size, shape, or organization of cells
or tissues.
• Hyperplasia and dysplasia may precede the appearance of a cancer by several months
or years.

24. • Malignant cells are divided into those of epithelial origin or the other tissue
types.
• Carcinomas are malignant growths arising from epithelial cells.
• Malignant growths of muscle or connective tissue are called sarcomas.
• An adenocarcinoma is a malignant tumor arising from glandular tissue.
• Another term used frequently in the description of malignancy is carcinoma
in situ.
• In this instance, the cancer is limited to the epithelial cells of origin; it has
not yet invaded the basement membrane.
• Carcinoma in situ is a preinvasive stage of malignancy, and most tumors
have progressed well beyond this stage at diagnosis.
• Like all classification systems, there are exceptions to these rules.
• Malignancies of hematologic origin, such as leukemias and lymphomas, are
classified separately.

25. TUMOR CHARACTERISTICS
• Tumors may be either benign or malignant.
• Benign tumors are noncancerous growths that are often encapsulated, localized, and
indolent.
• Cells of benign tumors resemble the cells from which they developed.
• These masses seldom metastasize, and once removed they rarely recur.
• In contrast, malignant tumors invade and destroy the surrounding tissue.
• The cells of malignant tumors are genetically unstable, and loss of normal cell
architecture results in cells that are atypical of their tissue or cell of origin.
• These cells lose the ability to perform their usual functions.
• This loss of structure and function is defined as anaplasia.
• In contrast to benign tumors, malignant tumors tend to metastasize, and consequently,
recurrences are common after removal or destruction of the primary tumor.

26. INVASION AND METASTASIS
• Metastasis is the spread of neoplastic cells from the primary tumor site to distant
sites
• Despite advances in diagnostic techniques and screening for cancer, many
patients have detectable metastatic disease at diagnosis.
• Once clinically evident distant metastases are present, cancers are seldom
curable.
• Newly diagnosed cancer patients may also have microscopic cancer metastases.
• Although clinically undetectable, these small clusters of diseased cells must be
present, because many patients subsequently relapse at distant sites despite
removal of the primary tumor.
• Some patients with micro metastatic disease may be cured with systemic
chemotherapy.

27. • The two primary pathways of metastasis are hematogenous and lymphatic.
• Other less-common modes of disease spread include dissemination via
cerebrospinal fluid and transabdominal spread within the peritoneal cavity.
• Tumors are constantly shedding neo plastic cells into the systemic circulation
or surrounding lymphatics.
• This process may begin early in the life of the tumor and often increases with
time.
• The time course for metastasis depends largely on the biology of the tumor.
• Breast cancer, for example, tends to metastasize very carly.
• Not all of the shed cancer cells, or "seeds." result in a metastatic lesion.
• The "seed" must first find the appropriate "soil" or an environment suitable
for growth.“
• This process is illustrated in the diverse patterns of metastasis that are
characteristic of individual types of cancer.

28. • An example is prostate cancer, which commonly metastasizes to bone, but
rarely to the brain.
• The process of invasion and metastasis involves several essential steps.
• After neoplastic transformation, the malignant cells and sur rounding host
tissue secrete substances that stimulate the formation of new blood vessels to
provide oxygen and nutrients.
• This process is known as angiogenesis or neovascularization.
• Tumor cells must then detach from the primary mass and invade surrounding
blood and lymph vessels.
• The tumor cells or cell aggregates detach and embolize through these vessels,
but most do not survive circulation.
• The disseminated cells must then attach to the vascular endothelium.
• The cells may proliferate within the lumen of the vessel, but most commonly
extravasate into the surrounding tissue.

29. • The local microenvironment may provide growth factors that can serve
as "fertilizer" to potentiate the proliferation of the metastasis.
• At every step of the way, the potential metastatic cell must fight the host
immune system.
• Last, the metastasis must again initiate angiogenesis to ensure continued
growth and proliferation.
• Because angiogenesis has been recognized as a critical element in
primary tumor growth as well as metastasis, it has become a target for
development of new anticancer agents.

30. DIAGNOSIS AND STAGING
• Screening
• Because cancers are most curable with surgery or radiation before they have metastasized, early
detection and treatment have obvious potential benefits.
• In addition, small tumors are more responsive to chemotherapy, as discussed previously.
• Early diagnosis is difficult for many cancers because they do not produce clinical signs or symptoms
until they have become large or have metastasized.
• Cancer screening programs are designed to detect signs of cancer in people who have not yet
developed symptoms from cancer.
• Lack of effective screening methods for some cancers and inaccessibility of some anatomic sites
further complicate the process.
• Education of the public on the early warning signs of common cancers is extremely important for
facilitating early detection.
• For some cancers, effective screening procedures do exist.
• The Papanicolaou (Pap) smear test, for example, is an effective tool to detect cervical cancer in its
early stages.
• Self-examination of the breasts in women and of the testicles in men may lead to early diagnosis of
cancers in these organs.

31. • The American Cancer Society has published guidelines for routine screening examinations

32. DIAGNOSIS
• The presenting signs and
symptoms of cancer vary
widely and depend on the
type of cancer.
• The presentation in adults
may include any of
cancer’s seven warning
signs, as well as pain or
loss of appetite.

33. • The warning signs of cancer in children are different and reflect the
types of tumors more common in this patient population.
• Even with increased public awareness, the fear of a cancer diagnosis
can deter patients from seeking medical attention.
• The definitive diagnosis of cancer relies on the procurement of a
sample of the tissue or cells suspected of malignancy and pathologic
assessment of this sample.
• This sample can be obtained by numerous methods, including biopsy,
exfoliative cytology, or fine-needle aspiration.
• A tissue diagnosis is essential, because many benign conditions can
masquerade as cancer.
• Definitive treatment should not begin without a pathologic diagnosis

34. STAGING AND WORKUP
• In addition to tissue diagnosis, tumors should be staged to determine
the extent of disease before any definitive treatment is initiated.
• The process is dictated by knowledge of the biology of the tumor and
by the signs and symptoms elicited in the history and physical
examination.
• Staging provides information on prognosis and guides treatment
selection.
• After treatment is implemented, the staging workup is usually
repeated to evaluate the effectiveness of the treatment.

35. • A staging workup may involve radiographs, computed tomography
scans, magnetic resonance imaging, positron emission tomography
scans, ultrasonograms, bone-marrow biopsies, bone scans, lumbar
puncture, and a variety of laboratory tests, including appropriate
tumor markers.
• Some cancers produce antigens or other substances that are
characteristic of that particular cancer.
• These so-called tumor markers are often nonspecific and may be
elevated in many different cancer types, or in patients with
nonmalignant diseases.

36. • As a result, tumor markers are generally more useful for monitoring response and
detecting recurrence than as diagnostic tools.
• Examples are the measure of human chorionic gonadotropin and alpha-
fetoprotein in patients with testicular cancer, or prostate-specific antigen in
prostate cancer.
• The most commonly applied staging system for solid tumors is the TNM
classification, where T-tumor, N= node, and M = metastases.
• A numerical value is assigned to each letter to indicate the size or extent of
disease.
• The designated rating for tumor describes the size of the primary mass and ranges
from T₁ to T.
• Carcinoma in situ is designated T.
• Nodes are described in terms of the extent and quality of nodal involvement (No
to N₁).
• Metastases are generally scored depending on their presence or absence (Mg or
M₁).

37. • To simplify the staging process, most cancers are classified according to
the extent of disease by a numerical system involving stages I through IV.
• Stage I usually indicates localized tumor, stages II and III represent local
and regional extension of disease, and stage IV denotes the presence of
distant metastases.
• The assigned TNM rating translates into a particular stage classification.
• For example, T,N M, describes a moderate to large-sized primary mass,
with regional lymph node involvement and no distant metastases, and
for most cancers is stage III.
• The criteria for classifying disease extent are quite specific for each
different type of cancer.
• For some tumors, alternative alphabetical systems (stage A, B. C. or D)
are used in clinical practice.