New findings suggest colorectal cancer origins are different than previously thought
(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.
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.
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.
The researchers found that:
· in cancer-bearing subjects the mucosal protein synthesis amounted to 1.28 ± 0.24%/h. This rate was significantly higher (P < 0.05) than the corresponding rate of mucosa from patients after cancer removal (0.69 ± 0.09%/h).
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.
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
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 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.