Group Title: Journal of Carcinogenesis 2003, 2:1
Title: Carcinogenesis: The more we seek to know the more we need to know – Challenges in the post Genomic Era
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Title: Carcinogenesis: The more we seek to know the more we need to know – Challenges in the post Genomic Era
Series Title: Journal of Carcinogenesis 2003, 2:1
Physical Description: Archival
Creator: Kovvali G
Shiff S
Telang N
Das K
Kohgo Y
Narayan S
Li H
Publication Date: 37652
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Volume ID: VID00001
Source Institution: University of Florida
Holding Location: University of Florida
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Journal of Carcinogenesis BioMed C



Editorial

Carcinogenesis: The more we seek to know the more we need to
know Challenges in the post Genomic Era
Gopala Kovvali* 1, Steven Shiff2, Nitin Telang3, Kiron Das1, Yutaka Kohgo4,
Satya Narayan5 and Honghua Li2


Address: 1Crohn's and Colitis Center of New Jersey, Department of Medicine, The University of Medicine and Dentistry of New Jersey Room 7023,
125 Paterson Street, Clinical Academic Building, New BrunswickNJ 08901, United States, USA, 2Department of Molecular Genetics, Micorbiology
and Immunology/Cancer Institute of New Jersey, The University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA, 3Strang
Cancer Prevention Center, New York, NY 10021, USA, 4Asahikawa Medical College, Asahikawa, Hokkaido, Japan and 5Department of Anatomy
and Cell Biology, University of Florida, Gainesville, FL 32610, USA
Email: Gopala Kovvali* kovvalgk@umdnj.edu; Steven Shiff shiffst@umdnj.edu; Nitin Telang telangn@rockefeller.edu;
Kiron Das daskm@umdnj.edu; Yutaka Kohgo ykl950@asahikawa-med.ac.jp; Satya Narayan snarayan@ufscc.ufl.edu;
Honghua Li holi@umdnj.edu
* Corresponding author


Published: 31 January 2003
journal of Carcinogenesis 2003, 2:1


Received: 2 January 2003
Accepted: 31 January 2003


This article is available from: http://www.Carcinogenesis.com/content/2/I/I
2003 Kovvali et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all
media for any purpose, provided this notice is preserved along with the article's original URL.


In spite of all the advances in the treatment of cancer and
knowledge of the processes responsible for this disease,
there is a gap in understanding the molecular events lead-
ing to cancer and mechanisms of action by anticancer
agents. Generally speaking, the field of carcinogenesis is
far from being completely explored. Many novel ideas and
concepts still need to be introduced into the field and the
results of several provocative experiments are yet to be dis-
seminated and shared. There is a need and greater scope
for multidisciplinary research in the field. A forum for ac-
celerated publication of results and a free access to such
publications are very important to the field. These are the
considerations that led to the birth of a new online jour-
nal, Journal of Carcinogenesis http://www.carcinogene-
sis.com. The journal will branch into six sections each of
which is headed by an editor who is an expert in that field.

Diet, Nutrition and Environmental Carcinogene-
sis
The notion that diet and nutrition influence the develop-
ment of cancer is not new but today, most scientists and
the lay public firmly believe that cancer risk is linked to di-
et. In 1937, Frederic L. Hoffman noted that "excessive nu-
trition" was an etiological factor in cancer as well as were
fatty and sweetened foods, white bread, and meat [1].
Armstrong and Doll published a landmark paper in 1975
examining cancer incidence and mortality rates world


wide in relation to consumption of specific dietary sub-
stances which suggested that fat, meat, and animal protein
consumption affected the incidence of and mortality from
certain cancers [2].

Despite a good deal of research, our understanding of the
identity of the food components that promote or prevent
cancer is not complete. Thus, one of the major goals of the
field of carcinogenesis is to discover time-efficient experi-
mental paradigms that accurately identify dietary factors
influencing prevention or development of cancer, and to
identify and validate biomarkers for cancer risk in all tis-
sues, particularly in those that give rise to the most com-
mon cancers such as lung, breast, colon, prostate, and
pancreas. One method of identifying biomarkers is to elu-
cidate the biological mechanisms by which dietary factors
influence carcinogenesis. Mechanistic understanding may
produce viable biomarkers, which, if validated, could
streamline the identification of substances that deserve
additional scrutiny.

Diet, Nutrition and environmental carcinogenesis section
of the new Journal, Journal of Carcinogenesis will publish
original research and review articles that advance our un-
derstanding of the fundamental linkages between diet and
cancer, especially those manuscripts that describe the de-
velopment or validation of novel biomarkers of carcino-


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genesis, define food or nutritional factors that affect
cancer development or elucidate the mechanisms by
which these factors influence carcinogenesis.

Chemoprevention
Cancers in the organs containing epithelial sites such as
breast, colon, prostate and lung represent major prevent-
able causes of mortality in the U.S. population [3]. Epide-
miological and laboratory investigations have provided
strong, but largely circumstantial evidence that naturally-
occurring dietary components may exert protective effects
against cancers in these organs in humans [2]. However, a
direct clinically relevant mechanistic significance of pre-
ventive efficacy for dietary natural phytochemicals de-
pends on extrapolation laboratory results.

Investigations focused on development of human tissue-
derived preclinical models, and on identification of mech-
anism-based genetic, molecular, endocrine and cellular
biomarkers specific for pre malignant lesions [4] may pro-
vide a viable approach for evaluation of novel naturally
occurring preventive agents [5-7]. Such approaches may
minimize the need for extrapolation of clinical efficacy of
new chemopreventive compounds. Promising agents
identified through these preclinical studies can then be
rapidly tested via conventional clinical trials.

The section on cancer chemoprevention in the Journal of
Carcinogenesis encourages submission of manuscripts that
are focused on development of novel model systems for
multistep organ site carcinogenesis, identification and
validation of new mechanistic surrogate endpoint bi-
omarkers for risk of carcinogenesis, and approaches for
high-throughput mechanistic screening of carcinogens
and cancer chemopreventive agents. We also welcome
manuscripts related to evaluation of preventive efficacy of
new naturally occurring and synthetic compounds.

Gastrointestinal Carcinogenesis
Gastrointestinal cancers are among the leading cause of
cancer deaths throughout the world. During the last dec-
ade, adenocarcinoma of the esophagus has been found to
increase most rapidly throughout the Western hemi-
sphere. Gastric adenocarcinoma is the second most com-
mon malignancy and cause of cancer related deaths
worldwide, particularly in Asian countries. Colorectal
cancer is the second leading cause of cancer deaths in the
United States. It is anticipated that 130,000-200,000 in-
dividuals in the United States will be diagnosed annually
with colorectal cancer, and more than 56,000 will die of
this disease. All of the three above carcinomas, arising
from the esophagus, stomach and colon proceed through
preneoplastic stages, which, if diagnosed early, would be
amenable to significantly improved, long-term survival of
the patients and possible cure.


A potential strategy to reduce the mortality rate of esopha-
geal adenocarcinoma is to identify patients at risk in early
stage. Increased COX-2 expression in vitro is associated
with increased cellular proliferation and decreased apop-
tosis. These findings may have implications for chemopre-
vention of adenocarcinoma of the esophagus. Similarly, a
novel monoclonal antibody called mAb Das-1 (7E12H12,
IgM isotype) has been found to be very sensitive and spe-
cific for early detection of metaplastic changes in the distal
esophagus and Barrett's epithelium, allowing more effec-
tive screening [8].

Inflammatory bowel disease, age, diet low in fiber and
high in fat, sedentary life style and of course familial inci-
dence are risk factors for colon cancer [9]. In the colon, ad-
enomatous polyp is a well recognized pre-cancerous
condition. The prevalence of adenomas in the United
States is approximately 25% by the age of 50 years, al-
though autopsy series suggest that as many as 60% of men
and 40% of women may have adenomas by 50 years of
age. Molecular genetic studies of Barrett's epithelium, gas-
tric intestinal metaplasia and colorectal tumors have pro-
vided significant insight into inherited predisposition and
possible clues in the pathogenesis. For colorectal tumors,
in particular, where such studies are done more extensive-
ly, accumulation of oncogene and tumor suppressor gene
mutations appear to be critical to tumor development
[ 10]. A relatively limited number of oncogenes and tumor
suppressor genes K-ras, APC, and p53 genes have been
found to be recurrently mutated in colorectal tumors and
intensive studies of the function of these critical genes in
normal and neoplastic cell growth continue. A number of
other genes, in which somatic mutations appear to be less
frequent, have also been identified. These include the P-
catenin, DCC, DPC4, SMAD2, TGFPIIR, MSH2, MLH1
genes. Changes in the expression of a variety of genes ap-
pear to have a crucial role in the development of cancer
and in its clinical course.

Despite significant progress, much work lies ahead before
we have a fully developed picture of the pathogenesis of
various gastrointestinal cancers. The significance of the
cancer cell phenotype of each of the inherited and somatic
mutation has not yet been clearly defined. It is very likely
that identification of additional oncogenes and tumor
suppressor genes together with histogenetic studies will
provide important information related to cellular meta-
plasia in the esophagus, stomach as well as colorectal can-
cers. At present, there is little understanding of the
relationship between dietary and environmental agents
associated with any increased risk of gastric and colorectal
cancers. The precise role of helicobacter pylori infection of
the stomach is also poorly understood. Nevertheless, a
hopeful outlook is that significant efforts made during the
last decade have provided important insights into the ge-


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netic and molecular basis of the esophagus, stomach and
colorectal cancers, which will help in the diagnosis, and
treatment of patients with these tumors.

We eagerly look forward to receiving the exciting work
from various contributors in the field of gastrointestinal
carcinogenesis. We are particularly interested in articles
that will impact our understanding of many of these can-
cers at the genetic and molecular level, which will signifi-
cantly influence the early diagnosis, and more effective
treatment of these patients.

Preclinical and clinical studies
At the beginning of the 21st century, we are experiencing
a great development in the field of cancer biology and
medicine because of the rapid progress of molecular biol-
ogy and genetics. In particular, the progress in carcinogen-
esis research has enabled us to develop some new
therapeutic and preventive strategies against cancer in ad-
dition to traditional chemotherapies. Such a significant
advance was possible largely due to the studies of tumor
cells at molecular levels during the last 10 years or so.
Studies on gene expression profile on the serial steps of
carcinogenesis may lead the way to develop effective ther-
apies, so called 'molecular target therapy'. One of the ex-
amples includes imanitib mesylate (Gleevec in the US,
Glivec outside the US), which is a specific inhibitor for ty-
rosine kinase in Philadelphia chromosome positive
chronic myeloid leukemia (CML) and gastrointestinal
stromal tumors (GIST) [11,12]. In the coming years, many
candidate drugs will be tested and used with the similar
concept and technology. Moreover, technological advanc-
es in the field of genomics and proteomics will also usher
in new era for the preclinical and clinical studies based on
individual and race differences.

In the Preclinical and Clinical Studies section of the jour-
nal, we welcome you to publish your exciting results in
the new era of cancer detection, therapy and prevention
from the standpoints of carcinogenesis. We will publish
results from original research that makes use of materials
from cancer patients to conduct clinical or preclinical
studies with a goal to develop new diagnostic and treat-
ment strategy. The manuscripts to be published in this sec-
tion will include results from the following categories. (a)
preliminary results from clinical studies that suggest the
potential for extensive future clinical studies and (b) re-
sults from experiments using surgical or biopsy specimens
for identification of biomarkers of carcinogenesis and
measure of efficacy of cancer therapy and potential targets
for anticancer drug development [13]. Authors who want
to submit hypothesis, ideas on translational research are
also encouraged to send their contributions.


DNA Damage and Cell Signaling
Environmental carcinogens interact with DNA, cause mu-
tations, if the function of critical genes is affected by mu-
tation, deleterious effects like cancer may occur [14].
During the past several years, significant progress has been
made in understanding the role of carcinogens in cancer
initiation and progression [15]. However, appropriate
prevention approached for carcinogen-initiated cancers
are still not in place. One of the reasons is the lack of suf-
ficient knowledge about the molecular mechanisms of the
interaction of carcinogens with genes and the role on
these genes in carcinogenesis.

Defects in one or several of the DNA repair pathways can
be a determining factor in accumulation of mutations in
critical genes involved in the initiation and transforma-
tion of normal cells [14]. In clinical practice many chem-
otherapeutic drugs are the DNA-damaging agents, which
induce cell death through apoptosis by increasing DNA
damage and decreasing DNA repair [16]. One of the ques-
tions of clinical relevance is how we can save normal cells
from DNA-damaging effects of the clinically useful chem-
otherapeutic drugs while increasing the killing of cancer
cells? Alternatively and ideally, drugs inducing apoptosis
without DNA damaging effect would be highly desired.
Addressing these issues will be of immense interest to the
readers of the Journal of Carcinogenesis.

We will also be interested in publishing those articles that
advance our understanding of how DNA damage signals
are coordinated among tumor suppressors and proto on-
cogenes and their gene products and how cell cycle con-
trol mechanisms are linked with DNA repair mechanisms
[17,18]. We invite papers pertaining to studies addressing
how cells exposed to DNA-damaging agents make deci-
sion on whether to go to 'safe mode' of cell cycle arrest
and call for help from DNA repair machinery or to save
the progeny by sacrificing themselves in an apoptotic way.
Journal of Carcinogenesis will publish articles devoted to
basic science and translational aspects of DNA damage
and cell signaling.

Genomics and Proteomics
Although many factors may contribute to cancer develop-
ment, cancer is a genetic disease and is caused by genetic
alterations in certain genes. Cancer development is associ-
ated with oncogene overexpression and inactivation tu-
mor suppressor genes (TSG). One of the causes of
oncogene overexpression is mutation in the regulatory re-
gions or in the genes encoding transacting factors that
have regulatory roles on oncogenes. However, the most
remarkable genetic alteration causing oncogene overex-
pression is gene amplification [19-21]. Oncogene ampli-
fication can be detected by using methods such as
Southern analysis [22] or Comparative Genomic Hybrid-


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ization [23] that may quantitatively reveal the gene dos-
age in the cells.

The other method that may have not been paid attention
to is genetic analysis. It is known that DNA sequence pol-
ymorphisms, especially, those consist of single nucleotide
sequence polymorphisms (SNPs), are present at a high
density along the chromosomes [24]. Because of such a
high density, many genetic markers are heterozygous for a
given patient and in a given chromosomal region. When
chromosomal amplification occurs, amplification may
not occur on both homologous chromosomes simultane-
ously. Even if it occurs on both chromosomes, the
number of resulting copies of an amplified region may
not be equal. In the cases that the difference is very big,
only one allele will be detected and the other will not or
almost not be detected. If the difference is not that big but
significant, one allele will be detected in a significantly
larger quantity. These will be considered as loss of hetero-
zygosity (LOH) or allele imbalance and can be conven-
iently detected by genetic approach that can be used to
discriminate the allelic differences.

TSG inactivation may be caused by various reasons. Muta-
tions that cause decrease in gene expression and/or result
in inactive gene products are some of the reasons. Howev-
er, since each cell contains two copies of these genes, the
chance of having both copies of a gene inactivated would
be very low. With its recognition in 1970 [25], LOH has
been shown, by a large number of studies, to play an im-
portant role in TSG inactivation, and may be used as a
common indication of TSG inactivation or oncogene am-
plification. LOH has been detected in a number of chro-
mosomal regions indicating the number of genes
involved in cancer development could be large. Exhaus-
tive identification of these genes, of course, is one of the
major goals for understanding cancer development,
which may take years of effort. However, the function of
these genes may be studied by correlating cancer mor-
phology and the respective chromosomal locations asso-
ciated with LOH without knowing the genes and their
products.

To be able to understand the genetic basis of cancer thor-
oughly, two major methodological issues need to be ad-
dressed. One is the high degree of heterogeneity in cancer
tissue. Many cancer tissues contain proliferative lesions
and more advanced malignancy, which may represent dif-
ferent stages of cancer development. On the other hand,
certain proliferative lesions or more advanced malignancy
may be categorized to be at the same development stages
but are present in distinct morphology. Studying these le-
sions and malignancy individually may allow one to learn
the stepwise involvement of the genes during cancer de-
velopment and different molecular pathways underlying


the distinct morphologies. For this reason, it is critical to
isolate and study these lesions and malignancy separately
using microdissection technique.

The other issue is the involvement of a large number of
genes with different chromosomal locations during can-
cer development. To include these genes in the study,
LOH analysis can be used as a common assay. However,
since the gene number is large and their chromosomal lo-
cations are different or unknown, it is necessary to per-
form a genome-scale analysis with genetic markers of a
high density, or in other words, with a large number of
markers. This has been made possible by the recent large-
scale discovery of SNPs. However, since the amount of
material from microdissection is very small, inclusion of a
large number of markers in the study is a serious chal-
lenge. Therefore, development of high-throughput assays
with high sensitivity is a critical step toward understand-
ing the genetic basis of cancer development in a compre-
hensive way.

During the past a few years, a large number of studies has
been performed to reveal changes in gene expression pat-
terns at either or both mRNA and protein levels. Many of
these studies were on a large or genomic scale. However,
the authors may have found difficulties to interpret their
data. Such an issue could be addressed by associate genet-
ic alterations in the cancer cells with the patterns from
gene expression profiling simply because genetic altera-
tions are the primary causes of changes in gene expression.
On the other hand, studies on gene expression profiling
will provide essential information on the effect of genetic
alterations, affected molecular pathways, and biomarkers
in these pathways, which maybe used conveniently for
monitoring cancer initiation and progression.

Since cancer is a genetic disease, it is critical to introduce
genetic approaches into cancer research. The Genomics
and Proteomics section of the journal will publish articles
describing using genetic approaches or combination of
genetic approaches and molecular and cytological ap-
proaches to addressing important issues in the field of car-
cinogenesis. We also welcome manuscripts describing
novel technological advances or refinements of existing
technologies that advance cancer research. In addition, we
will also be interested in publishing articles that present
results using any other novel technologies and contribute
to enhancement of our understanding of the processes of
carcinogenesis.

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