New Findings Do Not Support
Concept That Colorectal Cancer Originates From A Proliferative Disease Of
The Whole Colon
Increased mucosal protein
synthesis appears to depend on presence of the tumor itself, and
should therefore be considered a secondary phenomenon
(June 12, 2003) Bethesda, MD - Colorectal cancer
-- which includes cancers of the colon, rectum, anus, and appendix -- is the
second-leading cause of cancer-related deaths in the United States. The
mortality rate associated with this deadly disorder is well known. What is
not clear, however, is whether colorectal cancer should be considered a
local disease or a uniform organ disease that is not only localized at an
individual site along the colorectum.
Background
There is ongoing controversy over whether mucosal
hyperproliferation is involved in colorectal carcinogenesis. The hypothesis
that was originally offered to explain the transition from normal mucosa to
a benign epithelial neoplasm in which the tumor
cells form glands or gland-like structures used a three stage process.
At stage I, the proliferative compartment of the colorectal crypt,
which is usually confined to the lower one-third of the crypt, extends
upward and envelops the entire crypt. At stage II, the maximum of the
proliferative compartment shifts to the upper portion of the crypt, and, at
stage III, the total number of replicating cells in the crypt rises, leading
to mucosal hyperproliferation and subsequently -- due to the influence of
co-factors -- to a tumor. However, in patients with sporadic colorectal
cancer, findings are debatable, and the scientific literature is divided
into reports supporting or contesting the importance of the stage III defect
for adenoma and carcinoma formation.
One possible explanation for this discrepancy in
patients with sporadic colorectal cancer might be found in the techniques
used to evaluate mucosal proliferation. Most of these methods are applied in
vitro and are cytostatic, i.e., providing an estimate of only the fraction
of proliferating cells in a particular phase of the cell cycle at a given
moment. This information can be misleading, since it uses no measure of time
(length of the cell cycle). The duration of the cell cycle may, on the one
hand, be a major component of tissue proliferation and growth but is, on the
other hand, extremely difficult to examine in vivo because of the associated
invasive measures.
A New Study
A new study examines the protein synthetic rates as an
indicator of potential tissue proliferation in grossly normal rectal mucosa
derived from cancer-bearing subjects and compares this rate to the mucosa
from subjects after tumor removal. A research team has developed a technique
enabling them to perform dynamic proliferation measurements in vivo,
independent of surgery or anesthesia. This minimally invasive technique is
based on advanced stable isotope methodology and focuses on the
determination of the fractional protein synthetic rate as an indicator of
tissue proliferation.
Their study of tissue proliferation by measuring
protein synthetic rate is based on cell experiments that demonstrate a
direct correlation between the rate of cellular reproduction and cellular
protein synthesis. Experiments in transformed cells could show that an
increase of protein synthetic rate accompanies cell growth. Consequently,
artificial interruption of protein synthesis arrests cellular proliferation.
Besides other proteins, the increased protein synthetic rate in
proliferating cells occurs in proteins that control the growth process. In
malignant cells, these proteins are coded by protooncogenes.
The authors of “Effect of Tumor Removal on Mucosal
Protein Synthesis in Patients with Colorectal Cancer” are
Peter Rittler, Hans Demmelmair, Berthold
Koletzko, Karl-Walter Jauch, and Wolfgang H. Hartl, all from the
Dr. von Haunersches Kinderspital, Klinikum Innenstadt,
Ludwig-Maximilian University, Munich, Germany. Their findings appear in the
May 2003 edition of the American Journal of Physiology – Endocrinology
and Metabolism.
Methodology
Two groups of subjects, one with locally limited rectal
carcinoma (n = 6, three males, three females), the other after curative
surgery for colorectal cancer (control group; n = 5, three males,
two females), were studied. The groups were comparable in age (carcinoma:
67.3 ± 5.0 year; control: 64.5 ± 5.2), body weight (carcinoma:
70.0 ± 5.7 kg; control: 66.0 ± 4.2), height (carcinoma: 168 ± 3 cm; control:
165 ± 2), and body mass index (carcinoma: 25.0 ± 2.7 kg/cm2;
control: 24.3 ± 1.7). No participant had a history of previous weight loss
or clinical and laboratory signs of malnutrition or metabolic diseases.
The six postabsorptive patients with
localized rectal cancer and five postsurgical control subjects
received a primed constant infusion of [1-13C]leucine
(0.16 µmol/kg min, 9.6 µmol/kg prime). Forceps biopsies from the
mucosa were taken after three and six hours. Protein synthesis
was calculated from protein-bound leucine enrichment (determined
by capillary GC-combustion IRMS) and from the enrichment of free
intracellular leucine (determined by GC-quadrupole MS).
The free and protein-bound amino acids in tissue
biopsies were separated by precipitation of the proteins. After hydrolysis
of proteins, the researchers separated amino acids from the accompanying
impurities by cation-exchange chromatography. For capillary GC-combustion
IRMS analysis, amino acids from proteins were then converted to the
N-acetyl-n-propyl (NAP) ester. For GC-quadrupole MS analysis,
tert-butyldimethylsilyl (t-BDMS) derivative was prepared from free
intracellular amino acids. NAP-amino acid derivatives were analyzed in a
capillary GC-combustion IRMS system. Isotopomer ratios of the sample were
obtained by electron-impact ionization and selected ion monitoring at
mass-to-charge ratios and data were expressed as tracer-to-tracee ratios.
Results
The researchers found that:
Conclusions
Accordingly, these findings do not support the concept
that colorectal cancer originates from a proliferative disease of
the whole colon. Instead, increased mucosal protein synthesis
appears to depend on the presence of the tumor itself and should
therefore be considered a secondary phenomenon.
Additional Observations
This study is believed to be the first to demonstrate
in situ that mucosa from subjects after tumor removal demonstrates a
significantly lower rate of protein synthesis than does macroscopically
normal colorectal mucosa in patients with sporadic colorectal cancer. Since
this research compared mucosal protein synthesis after tumor removal with
that of tumor-bearing subjects in vivo, these data add much stronger and
more direct support to the hypothesis that tumor-associated mucosal
hyperproliferation of grossly normal mucosa in tumor-bearing subjects is
secondary to the presence of the tumor itself and disappears after tumor
removal. Thus, it is unlikely that patients with sporadic colorectal cancer
suffer from a generalized disease (stage III defect) that can be
demonstrated in the colorectum at a significant distance from the tumor. In
the latter case, local tumor removal would not have affected large bowel
protein synthesis.
This new knowledge will contribute to the ongoing
effort to find a cure for the deadly disease.
Source: May 2003 edition of the American Journal of Physiology
– Endocrinology and Metabolism
- end -
The American Physiological
Society (APS) was founded in 1887 to foster basic and applied science, much
of it relating to human health. The Bethesda, MD-based Society has more than
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***
Editor’s Note: A copy of the research article is
available in pdf format to the press.
Members of the press are invited to obtain a pdf copy
of the study and to interview members of the research team. To do so, please
contact Donna Krupa at 703.527.7357 (direct dial), 703.967.2751 (cell) or
djkrupa1@aol.com.
