Cellular Basis of Cancer: Cell Proliferation, Genetics, and Treatment

This essay provides a comprehensive overview of the cellular basis of cancer. It begins by explaining the normal cell cycle and its stages, followed by a discussion on how this cycle becomes disrupted in cancer cells, leading to unregulated proliferation and differentiation. The essay then delves into the characteristics of cancer cells, including their shorter generation times and reduced sensitivity to injuries. It also explores the process of metastasis, detailing how tumours invade and spread to other parts of the body. A significant portion of the essay is dedicated to molecular anomalies, focusing on the roles of oncogenes and tumour suppressor genes in cancer development. The essay concludes by highlighting the importance of understanding cellular kinetics for effective cancer treatment, emphasizing the impact of drug regimens and dosing schedules. The document includes references to relevant research papers and provides a detailed understanding of the biological mechanisms underlying cancer.

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Cellular Basis of Cancer
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Introduction:
At the cellular level, cancer is, in definition a deranged state of the normal cell proliferation
regulation cycle that occurs in the human system (Calabrese et al. 2007). The abhorrence occurs
in other cell cycle activities such as cell differentiation and death (Calabrese et al. 2007). The
normal cell growth cycle is, in fact, a series of states in which the cell exists (Cangul et al. 2002).
The existence of the cell in the various states is termed as the collective cell cycle (Calabrese et
al. 2007). Through this cycle, the processes of cell proliferation and differentiation (Calabrese et
al. 2007). These states have specific biochemical properties and vary morphologically (Calabrese
et al. 2007). The stages of the cell cycle are present in a continuum and thus there is no distinct
starting point or ending point (Cangul et al. 2002). These phases occur in a series and are in
continuous succession (Calabrese et al. 2007).
The normal cell proliferation cycle or the mitotic cell division process is responsible for cell
differentiation (Calabrese et al. 2007). In non-anomalous cells, the mitotic cycle consists of a G0
phase which is dubbed the resting phase (Calabrese et al. 2007). In the G0 phase, the cells are in
a resting state and are temporarily present in a non-proliferative state (Calabrese et al. 2007).
Upon stimulation, they transit into the G1 phase which is primarily for the synthesis of RNA or
proteins (Calabrese et al. 2007). It is also the primary pre-mitotic phase which then progresses
into the S phase (Calabrese et al. 2007). In the S phase, the synthesis of DNA occurs and the cell
transits into the G2 phase (Calabrese et al. 2007). The G2 phase is a relatively short-lived phase
and is the final preparatory phase for the onset of mitosis (Calabrese et al. 2007). The final stage
is that of mitosis where the actual cell division occurs (Calabrese et al. 2007). In the M phase
which is the mitotic phase, there are four distinct stages respectively (Calabrese et al. 2007).

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These sub-stages are termed the prophase, the metaphase, the anaphase, and the telophase
respectively (Calabrese et al. 2007). The conclusion of mitosis occurs with the process of
cytokinesis or the division of the cytoplasm (Calabrese et al. 2007). The resultant of cytokinesis
is the formation of two daughter cells with the exact DNA and cytoplasmic/cellular contents as
the mother cell prior to the mitotic division (Calabrese et al. 2007). The total time required for
the completion of one cell cycle in a quiescent cell is called the ‘generation time’.
Cancer: In definition, cancer is the state of unregulated cell proliferation (Calabrese et al. 2007)
(Cangul et al. 2002). Typically, the normal cell proliferation cycle becomes abhorrent and the
regulation of cell differentiation does not occur (Cangul et al. 2002). The salient features of this
cycle include a striking lack of mitotic division of cells (Cangul et al. 2002). Apart from this, the
cell differentiation cycle invades the neighbouring or adjoining tissue and more often than not
metastasis occurs. Typically, metastasis is the spreading of differentiated cells onto the
surrounding cells (Cangul et al. 2002). The spread of the cells occurs through the lymphatic
system or through the main bloodstream (Cangul et al. 2002). The immune system has a major
role in the elimination of cancers at the early stages since their onset upsets the homeostasis of
the body (Cangul et al. 2002). The immune system also likely plays a role in the detection of
premalignant cells (Cangul et al. 2002). The states of immunodeficiency are often associated
with a stark increase in the incidence of different cancer types (Cangul et al. 2002). This is
particularly true of cancers associated with viral infection, and tumours which have an origin in
the lymphatic system or skin (Cangul et al. 2002). Most of the cancers have a potential cure if
detected at an early onset stage (Cangul et al. 2002). In cases where the tumour is detected at
later stages of onset, long-term remission is a likely option (Cangul et al. 2002). In cases such as
breast cancer and prostate cancer, which are potentially life-threatening, when detected by

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mammography and prostate-specific antigen (PSA testing) at early stages have enhanced chances
of cure and treatment (Cangul et al. 2002). If the cancer is much advanced and cure is
improbable, the treatment would involve therapy, drugs, surgical procedures etc (Cangul et al.
2002). In cases where the patient has co-morbid conditions, the tolerance to these treatments may
be particularly low and the effect of cure may be compromised (Cangul et al. 2002).
Cell cycle in tumour cells (cancer):
Cells with malignancy, especially those of the lymphatic or bone marrow origin, may possess
shorter time periods of generation (Dai et al. 2011). In such cells, there are a reduced percentage
of cells present in the G0 phase (Dai et al. 2011). The tumour growth occurs in an exponential
trend in the initial stages and later the trend reaches a plateau (Dai et al. 2011). In this phase, the
rate of cell division i.e. synthesis of daughter cells is equal to the rate of cell death (Dai et al.
2011). The reduction in the rate of cell growth is likely due to the exhaustion of the nutrients and
oxygen supply that aid in cell growth and synthesis during the rapid expansion of tumour (Dai et
al. 2011). In comparison to tumours of larger surface area, the smaller tumours have more
number of actively dividing cells (Dai et al. 2011). In fact, the tumour cells have features similar
to the embryonic normal cells and divide actively in the same manner (Dai et al. 2011).
However, in non-embryonic cells, such division is pathological and leads to tumour progression
(Dai et al. 2011). These cells thus possess the ability to enter the proliferative phase just like the
embryonic cells (Dai et al. 2011). They have reduced susceptibility to injuries caused by
irradiation or drug exposure (Dai et al. 2011). In the design of drug regimens of the
antineoplastic category, it is of much importance to consider the cellular kinetics of specific
types of tumours (Dai et al. 2011). These characteristics will crucially impact the dosing
schedules and treatment intervals (Dai et al. 2011). The drugs of the antineoplastic and

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antimetabolite categories have the maximum effectiveness in the stage where active division of
cells is prevalent (Dai et al. 2011). Certain drugs have an increased efficiency in certain specific
stages of cell differentiation or cell cycle (Dai et al. 2011). Such drugs have to be administered in
prolonged dosages in order to determine the optimal stage for the drug to be effective (Dai et al.
2011). Thus the stage of maximum sensitivity to the drug can be determined (Dai et al. 2011). In
the treatment of cancer, thus, the knowledge of cellular kinetics for the progression and
development of tumour is indispensible (Dai et al. 2011).
Metastasis - tumour growth:
With the growth of the tumour, the tumour begins to derive most of the nutrients from the
circulatory blood (Dai et al. 2011). Enzymes such as proteases facilitate local growth of the
tumour and this growth affects the adjacent cells and tissues (Dai et al. 2011). The volume of the
tumour increases with tumour progression (Dai et al. 2011). Such an increase is accompanied by
factors of tumour angiogenesis (Dai et al. 2011). These factors include vascular endothelial
growth factor (VEGF) and they are produced by the tumours in order to promote the formation
of the vascular supply required for the further growth of the tumour (Dai et al. 2011). A tumour
may invade into the circulation since the time of inception (Dai et al. 2011). In patients of
advanced stages of cancer, tumour cells have been found in circulation (Dai et al. 2011). Most of
these circulatory cells die in the intravascular space itself (Dai et al. 2011). However,
occasionally, some of these cells may adhere to the vascular endothelium (Dai et al. 2011).
These cells may penetrate into the tissues surrounding the tumour tissue (Dai et al. 2011).
Therefore, at distant sites, independent tumours are generated i.e. metastases are formed (Dai et
al. 2011). Metastatic tumours also progress in a manner similar to the other tumours and
subsequently give rise to other metastases (Dai et al. 2011). Research has suggested that the

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crucial properties of metastatic cells include the ability of migration, invasion, and to implant and
stimulate the growth of new blood vessels successfully (Dai et al. 2011). These cells likely
represent a subset of cells present in the primary tumour (Dai et al. 2011).
Molecular anomalies:
Mutations in the genetic makeup are mostly responsible for the generation of cancer cells (Dai et
al. 2011). Thus, these cells are present in all types of cancer (Dai et al. 2011). Such genetic
mutations lead to the alteration of the quantity and the functionality of the products of the protein
(Dai et al. 2011). They also regulate the growth and division of cells along with altering the
repair of DNA (Dai et al. 2011). The two primary categories of mutations are mutations that
result in oncogenic genes and tumour suppressor genes (Dai et al. 2011).
 Oncogenes: These genes are in fact anomalous forms of normal genes (Dai et al. 2011).
They are thus termed proto-oncogenes and they regulate the various aspects of cell
growth (Dai et al. 2011). The mutations that lead to the formation of oncogenes often
lead to the continuous and direct stimulation of pathways such as cell surface growth
factor receptors, angiogenesis, other physiologic processes, cell division, and DNA repair
(Dai et al. 2011). An example of this is the RAS gene that encodes the ras protein. The
ras protein is a factor that carries signals starting from the membrane bound receptors to
the RAS-MAP Kinase pathway (Dai et al. 2011). This progresses onto the nucleus of the
cell and ultimately regulates the division of the cell (Dai et al. 2011). Mutations result in
the activation of the ras protein in an inappropriate manner which leads to the activation
of cell growth in an uncontrolled fashion (Dai et al. 2011). Particular oncogenes have
important implications on the prognosis, diagnosis, therapy, and disease progression (Dai

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et al. 2011). The formation of oncogenes is typically a result of acquired mutations of the
somatic cell which are secondary to the point mutations (Dai et al. 2011).
 Tumour suppressor genes: genes including the p53 gene are an important factor in the
normal division of cells and DNA repair (Dai et al. 2011). This factor is also crucial for
the repair of DNA and detection of DNA damage or abnormal growth signals (Dai et al.
2011). In the case where these genes lose the ability to function due to acquired
mutations, the system that monitors the integration of DNA becomes inefficient. This
further leads to the persistence and proliferation of cells that have spontaneous genetic
mutation resulting in tumours ultimately (Dai et al. 2011). More often than not, there are
two alleles that encode for each of the genes that result in tumour suppression (Dai et al.
2011). Sometimes, defective clones of any one gene may be inherited which leaves only
one allele which is functional for the individual tumour suppressor genes (Dai et al.
2011). When another allele acquires a mutation, the subsequent normal tumour
suppressor gene loses its protective mechanism (Dai et al. 2011). An illustration for this
concept lies in the retinoblastoma (RB) gene which encodes for the Rb protein and is
responsible for the regulation of the cell cycle with the termination of the replication of
DNA (Dai et al. 2011). In most human cancers, the mutations of the RB gene family
occur allowing the division of affected cells in a continuous process (Dai et al. 2011).
Another example of a regulatory protein is the p53 gene. It prevents the replication of the
DNA which is damaged in normal cells and leads to the death of the cell via apoptosis in
those cells that have abnormal DNA (Dai et al. 2011). p53 cells which are altered,
anomalous, or inactive allow those cells containing abnormal DNA to differentiate and
survive in the said condition (Dai et al. 2011). Mutations get passed onto the daughter

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cells in order to confer a high probability to replicate the DNA which is error-prone (Dai
et al. 2011). These lead to the results of the neoplastic transformation (Dai et al. 2011). In
most human cancer strains, the p53 gene is defective (Dai et al. 2011). In the case of
oncogenes, the mutation that occurs in the tumour suppressor genes such as p53 and RB
in most of the germ line cells usually likely result in the vertical transmission (Dai et al.
2011). The incidence of cancers in the offspring is also exponential (Dai et al. 2011).
Chromosomal abnormalities:
The overall abnormalities in the chromosomes most likely occur through mutations such as
deletion, duplication, and translocation (Driessens et al. 2012). In certain situations, such
mutations and alterations in the gene either activate or inactivate genes that instigate
abnormal proliferation of cells (Dai et al. 2011). In these situations, the development of the
tumour is initiated (Driessens et al. 2012). In most forms of human cancer, abnormalities of
the chromosome are inevitable (Driessens et al. 2012). Therefore, in patients with congenital
diseases such as Down syndrome etc., the risk of development of lymphomas and leukemia is
rather high, especially in children (Driessens et al. 2012).
Other cellular factors impacting cancer:
Most forms of epithelial cancers are most likely caused from a series of genetic mutations
that ultimately result in neoplastic conversion (Driessens et al. 2012). In the example of
familial polyposis, the development of the disease occurs through a series of genetic events
such as the hyperproliferation of the epithelium i.e. to the loss of a suppressor gene present
on the chromosome 5, adenomas (early, intermediate, and late) (Driessens et al. 2012). The
final stage is the development of cancer (Driessens et al. 2012). Adenomas progress in the

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order of acquiring changes in DNA methylation (early stage) to increased activity in the RAS
oncogene (intermediate stage) and finally the loss of a suppressor gene present on
chromosome 8 (late stage) (Driessens et al. 2012). For the occurrence of metastasis, further
changes in the cellular level occur (Driessens et al. 2012). Some of these changes in the cell
that lead to metastasis include activation of telomerase which inhibits the proliferation of
telomere by means of telomere shortening (Driessens et al. 2012). The activation of
telomerase thus results in a continuous and abnormal proliferation of telomeres in tumour
cells (Dai et al. 2011).

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Cangul, H., Salnikow, K., Yee, H.Z., et al. 2002. Enhanced overexpression of an
HIF-1/hypoxia-related protein in cancer cells. Environ Health Perspect, 110, pp. 783–8.
Dai, Y., Bae, K., Siemann, D.W. 2011. Impact of hypoxia on the metastatic potential of
human prostate cancer cells. Int J Radiat Oncol Biol Phys, 81, pp. 521–8.
Driessens, G., Beck, B., Caauwe, A., et al. 2012. Defining the mode of tumour growth by
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Fong, G.H., Takeda, K. 2008. Role and regulation of prolyl hydroxylase domain proteins.
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