Basic a n d B e h a v i o u r a l S c i e n c e s Indian J Pediatr 1997; 64:131-141

The Causes of Cancer : I m p l i c a t i o n s For Prevention

and Treatment
B.V. Madhukar and J.E. Trosko

Department of Pediatrics and Human Development, College of Human

Medicine, Michigan State University, East Lansing, Michigan, USA

Abstract. The final clinical manifestation of cancer is a result of complex series of changes
in a single cell. This review summarizes some of the new concepts and hypotheses that
explain the evolution of cancers. The emphasis is on cancer as a disease of the stem cells
within a tissue that undergo initiation as a result of mutational insult to one or more genes
that are critical for cell growth. During the second stage (promotion stage) the initiated cells
acquire proliferative capacity due to epigenetic changes, i.e., altered expression of genes
whose products play a central role in signal transduction. This requires continued exposure
to agents and events causing such changes. This stage is, therefore, reversible and the
various components of this stage are central targets for the development of mechanism based
anti-cancer drugs. During the stage of progression, the neoplastic lesions acquire additional
genetic alterations and become clinically manifestable malignant neoplasms. At the biochemical
and molecular level, neoplastic tranformation involves aberrations in the expression and
regulation of oncogenes, tumor suppression genes, transcription factors and components of
the cell signal transduction cascades. The understanding of the various cellular biochemical
and molecular events that metamorphose a normal cell into a cancer cell is central to the
development of rational new drugs that. are targeted against the various components. Such
drugs in combination with the conventional chemotherapeutic agents that are currently used,
provide a more effective control of cancer without the risk of toxic side effects.

Key words: Neoplastic growth; Multistage carcinogenesis; Oncogenes; Tumor suppressor

genes; Signal transduction.

Cancer is clearly a world-wide problem. molecular and cell biology, together with
With a p p r o x i m a t e l y one out of four both experimental animal and h u m a n
individuals having the chance of getting epidemiological data, have provided the
this disease before they die, it is clear, that foundation for new approaches to prevent
new insights are needed to understand the and treat cancers. More importantly a basic
nature of this disease both by the physician understanding of how a seemingly normal
and the society w h o m u s t deal w i t h cell metamorphoses into a cancer cell,
prevention and treatment both. M o d e m acquires unrestrained growth propensity
and d o d g e s b o d y ' s i m m u n e d e f e n s e
Reprint requests: Burra V. Madhukar, Ph.D. mechanisms to become a clinical tumor and
Department of Pediatrics/Human Development, how these changes can be detected early,
Michigan State University, East Lansing, Michigan, before the clinical manifestation of cancer,
USA. is critical for the development of new
132 TIlE INDIAN JOURNAL OF PEDIATRICS
therapeutic regimes to combat the disease
in its v e r y early stages. Clearly such
a p p r o a c h e s are beneficial for both
psychosociological and economic reasons.
In this review, we focus on the basic biology
of the cancer cell, its genesis from a normal
cell and the biochemical and molecular
events that facilitate the metamorphosis of
a normal cell into a cancer cell. For obvious
reasons, it is not possible to give a detailed
description of each of these events in this
short review; we will briefly highlight the
critical events in cancer cell growth and
explain how such information is useful for
the development of new cancer therapeutic
strategies. Many of these new concepts and
techniques must be understood in order
that effective strategies and treatments for
cancer be developed and applied.
These concepts include: (a) "multi-
stage, multi-mechanism" or the "initiation/
promotion/progression" theory of cancer
formation; (lo) the "stem cell" theory of
cancer; (c) the "oncogenes and t u m o r
suppressor genes" in cancer; (d) "signal
transduction'; (e) " a p o p t o s i s " or
programmed cell death; and (f) "nature and
nurture" theory of cancer formation. While
each concept is based on strong scientific
evidence, it is, by itself, i n c o m p l e t e .
Therefore, ultimately, an integration of all
of them will be necessary to d e v e l o p
meaningful strategies of public policy and
clinical interventions.
MULTI-STAGE, MULTI-MECHANISM NATURE OF
THE CANCER PROCESS
The common misconception is that a single
exposure to a physical or chemical agent
will cause cancer. In truth, the transition of
a normal cell to a malignant, invasive and
metastatic cancer cell involves a complex
1997; Vol. 64: No. 2
set of interactions b e t w e e n the genes,.
development stage, the sex the environment
dietary factors, life style behaviours, work
place hazards, medications, and pollutants.
No one factor causes cancer. From both
animal experimental and human
epidemiological studies, the concept of
initiation, promotion, and progression
stages of the complex cancer process has
been developed. 1,~As shown in Fig. 1, when
a single cell (the stem cell as explained
below) is exposed to a physical or chemical
agent, such as ultraviolet light from the sun,
an irreversible change can be induced in
certain genes (e.g., oncogenes or tumor
suppressor genes, see b e l o w ) w h i c h
prevents the stem ceil from completing its
ability to terminally differentiate but not
from proliferating. These cells can partially
differentiate but are unable to lose their
ability to p r o l i f e r a t e u n d e r n o r m a l
conditions. These cells are not yet malignant
but have the potential to become cancers.
All human beings have "initiated" cells in
their body. However, these "initiated" stem
ceils can either be s u p p r e s s e d b y
surrounding normal cells, stimulated to
p r o l i f e r a t e or i n d u c e d to di~ b y the
induction of terminal differentiation or by
apoptosis (see below).
The process by which this irreversible
change or "initiation" occurs is thought to
be mutagenesis. Agents that can induce.
DNA damages and cause the formation of
an a b n o r m a l " o n c o g e n e " or " t u m o r
s u p p r e s s o r g e n e " are r e f e r r e d to as
"mutagens". If these "initiated" cells with
a m u t a t e d " o n c o g e n e " or " t u m o r
s u p p r e s s o r " gene are s u b s e q u e n t l y
stimulated to proliferate either by ncrmal
growth factors (as might happen in a young
child), by wound healing [actors (as might
h a p p e n after surgery, b u r n s , alcohol
1997; Vol. 64: No. 2 'II-IE INDIAN J O U R N A L OF PEDIATRICS 133

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134 THE INDIAN JOURNAL OF PEDIATRICS
induced liver damage, virus-induced cell
killing), or by exposure to chemicals that
induce cell p r o l i f e r a t i o n or p r e v e n t
programmed cell death (apoptosis), then a
clone of undifferentiated cells accumulates
in the tissue. This process is called tumor
promotion. Papilloma of the skin, the
nodule in the breast, the polyp in the colon
or the foci in the liver are examples of pre-
malignant initiated stem cells. Agents that
are t u m o r p r o m o t e r s are basically
mitogens, not mutagens2 They are capable
of inducing Signal transduction within the
cell (see below). This process of tumor
p r o m o t i o n is very d i f f e r e n t from the
initiation process, in that, it m u s t be
sustained for a longer period of time to
allow the single initiated stem cell to grow
into a large mass of cells (preneoplastic
lesion). This is to allow other additional
stable changes in other genes to convert the
non-differentiated abnormal stem cell to
acquire the properties of overcoming the
suppressing effect of proliferation within
and outside of the cell. In other words, the
promotion process is p o t e n t i a l l y
interruptable, if not reversible.
If sufficient numbers of initiated cells
are promoted, the probability is that enough
stable changes can occur in at least one of
these cells in the benign tumor such that
the cell no longer has its growth suppressed
by its own tumor suppressor genes or by
s u r r o u n d i n g normal ceils. It can now
invade the surrounding tissue and migrate
to distant tissues. At this point, it can be
said the cell has p r o g r e s s e d to the
malignant state. This process also seems to
involve a stable, irreversible set of changes
in its oncogenes or tumor suppressor genes.
This complex process by which a normal
stem cell evolves to the malignant state
involves multiple molecular/biochemical
1997; Vol. 64: No. 2
mechanisms at each stage of initiation/
promotion and progression. Conceptually,
it should be possible to intervene at each
stage to prevent the cancer process from
completion.
STEM CELL THEORY OF CANCER
In the h u m a n body, there exists
approximately 100 trillion cells. However,
from a n u m b e r of animal and h u m a n
studies, it is clear that all the cells of a given
tumor are derived from a single cell. In
other words, when the process of cancer
formation or carcinogenesis begins, a single
normal cell which has the potential to
proliferate and to differentiate somehow, is
unable to regulate its ability to stop cell
d i v i s i o n a n d its ability to t e r m i n a l l y
differentiate. After the complex series of
m o l e c u l a r / b i o c h e m i c a l a n d cellular
changes that occur d u r i n g the cancer
process, that single cell multiples many a
times and changes its genetic (genotype)
and physiological (phenotype) make up
such that it can multiply without restraint,
invade through tissues and metastasize to
other tissues.
What is the biological make up of the
cell that is the target for neoplastic growth?
In the human body, there exist four kinds
of cells - a few toti-potent stem cells (cells
that can give rise to all the cells of the body);
pluri-potent stem cells (cells which give rise
to all the cells of a given tissue or organ);
committed stem cells (cells that give rise to
one of few cell types in a given tissue or
organ); and the terminally differentiated
cell (highly specialized cells which can no
longer proliferate). Not all of these cells are
targets for the cancer process. Terminally
differentiated red blood cells, lens cells of
the eye, keratinocytes or neurones cannot
1997; Vol. o4: No. 2
give rise to cancers. However, the stem cells
of these differentiated cells are the targets
for this process. The normal function of the
stem cells within a tissue is to replace the
terminally differentiated dead cells. Thus,
in tissues s u c h as the skin w h e r e the
keratinocytes slough off as s q u a m e (dead
skin cells), f u n c t i o n a l k e r a t i n o c y t e s are
p r o d u c e d as a r e s u l t of s t e m cell
differentiation from the basal layer of the
skin. T h i s is a n e x a m p l e of r a p i d l y
proliferating and differentiating stem cells.
On the other hand, in tissues such as the
liver, stem cells are d o r m a n t but can rise
to t h e o c c a s i o n to p r o l i f e r a t e w h e n
warranted. Thus, it is clear that stem cells
of m a n y t i s s u e s are n o t a c t i v e l y
proliferating cells but have the potential to
do so w h e n the n e e d arises. The idea that
c a n c e r s o r i g i n a t e f r o m s t e m cells was
conceptualized b y the idea of " o n c o g e n y
as partially blocked o n t o n g e n y " . * In other
words, a normal stem cell when exposed
to a physical or chemical factor that can
prevent a single stem cell from terminally
differentiating but not from proliferating
can e v e n t u a l l y give rise to a malignant
cancer. As h u m a n s age, the n u m b e r of stem
cells in specific organs that are exposed to
agents that can start the cancer process
i n c r e a s e s . Also, s o m e o r g a n s , such as
h u m a n breast tissue, can have the stem cell
population decreased, thereby, decreasing
the p r o b a b i l i t y of h a v i n g c a n c e r (e.g.,
pregnancy at early ages tends to protect
against breast cancer).
ONCOGENES AND TUMOR SUPPRESSOR GENES
If the s t e m cell is a t a r g e t for the
carcinogenic process, the next question is
how is it affected during the initiation stage
of carcinogenesis? Obviously such a change
THE INDIAN JOURNAL OF PEDIATRICS 135
must sustain the proliferative competence
of the stem cell and block its ability to
differentiate. In m a n y cancers, mutations
have been found to occur in cellular genes,
the proto-oncogenes and tumor suppressor
genes, s-8 Here, we will briefly describe the
involvement of these two types of genes in
cancers.
Oncogenes
The growth, proliferation and
differentiation of normal cells involves the
concerted functioning of a n u m b e r of gene
products. The expression of these genes is
temporally very tightly regulated during
normal cell growth and proliferation. Such
genes are termed protooncogenes. In cancer
initiated cells these genes are deregulated
as a result of mutation or other initiating
insult. In m a n y cancers, a n u m b e r of such
genes have been identified and are termed
oncogenes meaning that their expression
causes cancer. A mutation occurring in a
normal proto-oncogene can constitutively
a c t i v a t e it so t h a t the r e g u l a t o r y
mechanisms in the cell are no longer able
to regulate it. This aberration can then turn
on the d o w n s t r e a m elements of the cell to
keep the proliferative signals continuously
active. As a result, these cells proliferate at
an accelerated pace than the normal cells
surrounding t h e m to g i v e rise to
preneoplastic lesions. Oncogenes that have
been reported to be aberrantly expressed
in h u m a n and experimental cancers are src,
ras, neu etc. 9 The protein products of these
genes, as will be explained later, are central
elements in cell signalling pathways that
r e g u l a t e g e n e e x p r e s s i o n a n d cell
proliferation. Some of these oricogenes code
for g r o w t h f a c t o r s , g r o w t h r e c e p t o r s ,
t r a n s d u c e r s of g r o w t h factor signals or
136 THE INDIAN JOURNAL OF PEDIATRICS
transcription factors that regulate gene
expression.l~
Tumor Suppressor Genes
While activation of oncogenes is frequently
found in cancers, somatic cell fusion
experiments between tumor and normal
cells h a v e s u g g e s t e d the presence of
suppressor genes in normal cells. 13 The
hybrid cells exhibited normal phenotype
and were not tumorigenic. This implied that
normal cells contain a dominant gene that
can suppress tumor cell growth. In tumor
cells, these genes are inactivated. Such
genes are termed tumor suppressor genes
or a n t i o n c o g e n e s . One of the first
discovered tumor suppressor genes is the
r e t i n o b l a s t o m a (Rb-1) gene that is
r e s p o n s i b l e for r e t i n o b l a s t o m a s in
children} ~ Retinoblastomas result from the
mutational inactivation of the Rb-1 gene.
From various studies it appears that the
RB gene functions as a negative regulator
of cell proliferation through its effect on
cell cycle. Inactivation of Rb-1 gene is also
detected in other cancers such as lung
cancerJ s
A second tumor suppressor gene that
was intensively investigated was p53. Wild-
type p53 in normal cells is associated with
regulation of cell cycle. Mutations of the
p53 gene alter the ability of the gene
product so that it loses its ability to bind
with genes that negatively control cell
proliferation. I~ It is noteworthy that p53
m u t a t i o n s are seen in m a n y cancers
suggesting that p53 may be a common
biochemical p a t h w a y of diverse cancer
types.
SIGNAL TRANSDUCTION AND ONCOGENESIS
Normal cellular homeostasis depends on
1997; Vol. 64: No. 2
the hormonious response of cells to both
extracellular and intracellular stimuli and
this is important for the cells to carry out
physiological functions. That iS, a normal
cell responds to these stimuli in an ordered
manner that is strictly regulated. These
stimuli also regulate the way in which cells
grow and proliferate by triggering the
activity of a number of biochemical events
collectively called "signal transduction
cascades,, 17,18 In a cell that is destined to
b e c o m e cancerous, these s i g n a l l i n g
mechanisms are deregulated such that the
signal(s) generated for cell proliferation are
not turned off. These changes occur during
the promotion stage of tumorigenesis to
facilitate clonal expansion of cancer cell to
form a preneoplastic lesion. Briefly, cells
respond to various extracellular signals
such as growth factors by transducing the
signal through a number of cytoplasmic
elements and into the celJ nucleus. Signal
quenching occurs as a result of activation
of p r o t e a s e s a n d p h o s o p h a t a s e s and
prevents the signals from p r o c e e d i n g
u n a b a t e d . The various cellular signal
transduction pathways and their
interrealtionships are illustrated in Fig. 2.
It is quite obvious from the illustration that
the oncogenes that are usually activated
during neoplastic growth are, in fact, part
of the signal transduction cascades. For
example, the oncogene ras, when activated
by a mutation in one of the amino acids,
is locked in GTP bound state and sustains
the signals to the downstream elements of
the s i g n a l l i n g p a t h w a y s . Similarly,
activation of the oncogene n e u normally
found in human breast cancers can sustain
the tyrosine kinase activity of the signal
transduction pathway. It is also important
to note t h a t the v a r i o u s o n c o g e n e s
collaborate in the t r a n s d u c t i o n of the
1997; Vol. 64: No. 2 THE INDIAN JOURNAL OF PEDIATRICS 13 7

Growth
factors G'~
factor I I N~
receptors -
receptor
kinases -
e.g.
PDGF erbB, kit src GTP-R'---~

in

?- :ription factors
n, myc, etc.
[
~
, ,
]transcriotion I- '~translation

Nucleus ]
VY
]

cell proliferation ]

Fig. 2: Growth factors, oncogenes and components of cell signalling cascades in growth control and
as potential targets for anticancer drug intervention. Oncogenes code for growth factors, or growth
factor receptors, components of cell signalling cascades or nuclear transcription factors. The normal
regulatory controls over these oncogene products are ineffective because of mutations or over expression
of these genes. In turn, they interact (oncogene cooperativity) as well as affect other components of
the signal transduction cascades such as the second messenger systems (the protein kinase C pathway)
or MAP kinases (through the activation of raf-I oncogene) resulting in aberrant growth regulation.
Abbreviations: PDGF--platelet derived growth factor/sis oncogene; PI PLC -y- Phosphotidyl inositol
specific phospholipase C; DAG - diacylglycerol; IP3 - - inositol triphosphate; MAPK/MAPKK - mitogen
activated protein kinase/kinase; PKA cyclic AMP dependent protein kinase. The numbers indicate
components of the pathways that can be regulated by pharmacological intervention.
138 THE INDIAN JOURNAl, OF PEDIATRICS
proliferative signals to the nucleus. An
important aspect of the aberrant activity of
the signal ~.ransduction machinery is the
increase in the production of two important
second messengers, inositol triphosphate
and diacylglycerol that increase
intracellular calcium and activate protein
kinase C (PKC) respectively. PKC plays a
central role in the r e g u l a t i o n of the
d o w n s t r e a m e l e m e n t s of the signal
transduction cascade and activation of
transcription factors.
Communication Disorder of Cancer Cells
To maintain homeostasis, the various cells
within a tissue must communicate with
each other. M a n y cells do h a v e such
c o m m u n i c a t i o n channels t e r m e d gap
junctions. Gap junctions [connexions] are
protein channels that bridge the cytoplasm
of one cell with other neighboring cells in
contact. It is presumed that cells exhange
i n f o r m a t i o n m o l e c u l e s t h r o u g h gap
junctions. We now know that molecules
such as n u c l e o t i d e s and inositol
triphosphate and ions such as calcium can
pass t h r o u g h gap junctions. These
molecules are also recognized as important
in growth control. Thus it is obvious that
cancer cells might overcome the growth
constraints within a tissue environment if
their gap junctional communication with
the surrounding normal cells is abrogated.
Indeed, it has been shown that many cancer
derived cells and cancer cells in vivo do not
have functional gap junctions. Some cancer
cells do h o w e v e r , show the ability to
c o m m u n i c a t e a m o n g s t t h e m s e l v e s as
revealed by dye transfer assays. When
cultured with normal cells, however, they
fail to establish communication with the
former. This suggests that in addition to
1997; Vol. 64: No. 2
gap junctions, other gap junction associated
molecules or proteins are also important in
maintaining intercellular communication. A
calcium dependent protein, E-cadherin has
been s h o w n to be i n v o l v e d in the
recognition of cells and in junctional
communication. It is noteworthy that the
above described signalling mechanisms that
are aberrantly regulated in cancer cells
appear to affect gap junctional
communication suggesting that they may
converge upon gap junctional proteins as
a common target during neoplastic growth.
This raises the possibility that the growth
of cancer cells m a y be interfered by
upregulating their communication
proficiency with normal cells through
chemotherapeutic approaches. 19.2o Indeed,
gap junctional c o m m u n i c a t i o n can be
upregulated by caratenoids and agents that
elevate intracellular c-AMP. Interestingly
both caratenoids and c-AMP have been
used as potential anticancer agents2 ~ 21
APOPTOSIS AND CANCER
An important regulator of normal growth
and development, is a process termed
programmed cell death or "apoptosis"
t h r o u g h w h i c h u n w a n t e d cells in a
d e v e l o p i n g tissue are r e m o v e d . Thus,
during embryonic palatogenesis, the medial
epithelial cells of the two upper palatal
shelves undergo programmed cell death to
facilitate fusion of the two shelves. Cell
death is preceded by significant biochemical
changes in the apoptotic cells that results
in the degradation of DNA and chromatin
condensation. We do /lot yet know the
complete picture of the apoptotic process
but it is reasonable to assume that the
expression of certain new genes is involved.
In neoplastic cells, one can assume that
1997; Vol. 64: No. 2
apoptosis is inhibited. This assumption is
supported by the finding of a new gene,
the bcl-2 that was found to be expressed
in human follicular lymphoma.22 How bcl-
2 e x p r e s s i o n l e a d s to a b r o g a t i o n of
apoptosis is not yet known. The localization
of bcl-2 protein in mitochondria, nuclear
m e m b r a n e and endoplasmic reticulum
suggested that bcl-2 may function as an
antioxidant in the cells that may protect the
cells from apoptotic injury induced by
reactive oxygen species. Pharmacological
agents that selectively induce apoptosis are
likely to be of significant value as new
anticancer agents.
NATURE AND NURTURE OF GENES AND
ENVIRONMENT IN CANCER FORMATION
One of the common misconceptions is that
cancer is caused by either one's genes or
by the environment. In fact, all cancers are
the result of a complex interaction of
specific genes (oncogenes and t u m o r
s u p r e s s o r genes) and the specific
environmental factors of the individual. All
of us inherit "proto-oncogenes" (normal
genes of the cell n e e d e d for cell
proliferation and differentiation) and
"tumor suppressor genes" (normal genes
of the cell needed for normal suppression
of cell growth and for differentiation or
programmed cell death). We are all exposed
to physical and chemical agents that have
the potential of initiating, promoting or
causing progression of cells to become
tumors. Yet only one out of four of all
humans get a malignant tumor before they
die. Some get cancers early in life while
most get later. A few get multiple numbers
and kinds of tumors.
The " n a t u r e and n u r t u r e " concept
implies that both genes and environmental
THE INDIAN JOURNAl. OF PEDIATRICS 139
factors are needed to trigger a stem cell to
become initiated, promoted or progressed.
In other words, a person could inherit a
mutated gene which either predisposes
them to become initiated or promoted more
easily than a person who does not inherit
this mutated gene. Examples would include
the Xeroderma p i g m e n t o s u m , D o w n ' s
S y n d r o m e , R e t i n o b l a s t o m a , BRCA-1,
Wilms's, Bloom's, Fanconi's syndromes. In
the case of x e r o d e r m a p i g m e n t o s u m ,
syndrome, the individual inherits a mutated
gene for its ability to repair ultraviolet light
induced DNA damage to the skin cells. As
a result, either or both their oncogenes and
tumor suppressor genes in the cells of the
skin could be mutated (i.e., initiated). Sun-
light induced killing (apoptosis of their skin
cells, but not their initiated skin stem cells)
stimulate wound healing of the skin with
these initiated cells, leading to papillomas.
Continued exposure of these initiated
papilloma cells to ultraviolet light could
then lead to many skin cancers seen in these
y o u n g patients. On the other h a n d ,
a v o i d a n c e of s u n l i g h t by Xeroderma
pigmentosum patients would reduce the
skin cancers, in spite of the fact that they
carry the mutated DNA repair gene in all
their cells.
While modern molecular biology has
been able to identify more and more of the
genes predisposing individuals to cancer
(the "nature" part), unfortunately, we either
do not know what the specific "nature" or
environmental factors are that work with
these genes or we cannot control these
factors as we could with the Xeroderma
pigmentosum patient. For example, if a
person inherits a gene that is already
"initiated" or if all the cells of this person's
body are exposed to either their own
"promoter" (i.e., growth factor or hormone)
140 THE INDIAN JOURNAL OF PEDIATRICS
or to some ubiquitous chemical that is
impossible to escape, then it will be very
difficult to prevent the cancer.
In principle, there are genes that can
be initiation-prone, promoter-prone and
progressor-prone or predisposing genes.
These individuals will inherit genes that
make them very sensitive to physical or
chemical agents which can either mutate
oncogenes and tumor suppressor genes or
can cause initiated cells to proliferate. These
individuals tend to have tumors early in
life and multiple numbers and types of
tumors. This is why getting good family
histories in all cancer cases is important.
INTEGRATION OF CONCEPTS FOR CLINICAL
PREVENTION AND TREATMENT OF CANCER
In the f o r e g o i n g brief discussion, we
summarized the various mechanisms of
neoplastic growth. While the ultimate
cancer cell of various types of tumors may
have undergone drastic changes, there are
a few checkpoints at which intervention
through the use of pharmacological agents
is possible. These a l o n g w i t h the
conventional anticancer drugs may be more
useful than the use of conventional drugs
a!one. First, with the continued use of
conventional cytotoxic drugs, the problem
of resistance will be encountered. Second,
many of the currently used anticancer drugs
have serious side effects because of the
toxicity at the,concentrations (doses) they
are administered. On the other hand, in
c o m b i n a t i o n t h e r a p y of c o n v e n t i o n a l
anticancer drugs and drugs targeted against
cell s i g n a l l i n g m e c h a n i s m s , one can
eliminate the problem of side effects.
Because of the synergistic interactions
between these two types of drugs, they only
need to be administered at low doses that
1997; Vol. 64: No. 2
are not overtly toxic. However, one might
ask the question--does interference with
key signal transduction cascades disable
normal cell? The answer to this question is
no, since normal cells do not depend only
on one path w a y to m a i n t a i n cellular
homeostasis. There is ample redundancy in
the signal transduction pathways to enable
cells to function normally u n d e r such
situations.23, 24 On the other h a n d , in
neoplastic cells generally one or two
aberrations occur. Therefore, inhibiting their
function is likely to affect the cancer cell
w i t h o u t j e o p a r d i s i n g the f u n c t i o n a l
integrity of normal cells.
In light of the fact that the process of
tumorigenesis is a multistep process that
involves a complex array of change both
at genome and epigenetic levels, future
development of cancer control sirategies
must take into account the aberrations that
occur in the signal transduction cascades
of cancer cells. There has already been some
progress in using inhibitor drugs for specific
components of the signal transduction
pathways to prevent cancer cell growth. For
example, inhibitors of protein kinase C and
tyrosine kinases are being investigated as
anticancer agents in experimental models
and in early clinical studies. 2s
In short, human cancers arise as a result
of complex changes at the genomic and
epigenetic level of organization of cells
within a tissue. Such changes involve cell
signalling cascades that resist normal
control mechansims. Future anticancer drug
development should, therefore, focus on
drugs targeted to inhibit the aberrant
activation state of these pathways. With
increased understanding of the cancer cell
biochemistry and molecular biology we can
hope to develop drugs that specifically kill
cancer cells without affecting normal cells.
1997; Vol. 64: No. 2
ACKNOWLEDGMENTS
Supported by grants from the National
I n s t i t u t e s of H e a l t h ES-04911 a n d CA-21104
(JET).
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