Colorectal
Cancer: An Amalgam of Failures, Progress, and Prospects
Few biological puzzles are
more intriguing than colorectal cancer. While the disease is common and appears
to occur sporadically, familial syndromes are well documented. Tantalizing clues
concerning the relationship between diet and colorectal cancer have been studied
for years, but the incidence of the disease has not decreased despite wide public
education of these associations. Colorectal cancer has afforded researchers
a particular advantage for study because all of the malignant tumors have arisen
from a precursor lesion, the adenoma.[1] Yet, only some adenomas develop into
cancers, while others stop growing or regress. The adenoma-to-carcinoma sequence
has profound implications for screening strategies and early intervention programs.
More importantly, the sequence provides a unique opportunity for the molecular
biological understanding of the process in which adenomas, and then cancers,
arise from normal mucosa. Finally, this sequence of development suggests that
chemical intervention in the progression of normal mucosa to cancer may prevent
colorectal cancer.[2]
Once a cancer of the large
intestine has arisen, there are several characteristics of its tumor biology
that are unique. These tumors often release carcinoembryonic antigen (CEA),
which can be a useful serum marker for recurrence. Adjuvant chemotherapy affords
survival advantage for some stages of the disease. Surgeons have learned that
the colon can be removed via the laparoscope. Hospital stays after these less
invasive resections are shorter, but concerns about adequacy of resection and
tumor recurrence in operative port sites have not yet been resolved by careful
prospective study. Finally, a remarkable subset of patients with metastatic
colorectal cancer, those with spread limited to the liver, appears to enjoy
long-term survival after resection of metastatic deposits.[3]
Most exciting, however,
are the genetic changes that have been identified in colon cancer. Several oncogenes
have been implicated in the adenoma-carcinoma sequence. Various ras gene
mutations have been found in approximately 50% of colorectal cancers, but less
than 10% are found in adenomas less than 1 cm in diameter.[4,5] C-myc
proto-oncogene products, which appear to increase transcription, are elevated
in as many as 70% of colon cancers.[6-8] Tumor suppressor genes also may play
a prominent role in the development and spread of colorectal cancer. More than
75% of colon cancers are missing a large segment of chromosome 17p, a region
known to contain the p53 gene.[9,10] Another candidate tumor suppressor gene
that is located on chromosome 18q is commonly lost in colon cancers and has
been named the DCC (deleted in colon cancer) gene .[11,12]
Although the inherited forms
of colorectal cancer - familial adenomatous polyposis coli (FAP) and hereditary
nonpolyposis colorectal cancer (HNPCC) - together make up only approximately
6% of the colorectal cancers cases occurring each year in the United States,
patients with these two disorders have proven to be rich sources of material
for genetic study. A tumor suppressor gene associated with FAP has been mapped
to chromosome 5q and has been called the adenomatous polyposis coli (APC) gene.
Its product appears to bind to catenins, which are proteins that bridge the
cytoskeleton to E-cadherin, an intracellular adhesion molecule.[6] The interruption
of E-cadherin to catenin-binding might alter cell adhesion and contribute to
tissue invasion by cancer. HNPCC appears to be associated with an alteration
of normally found mismatch repair genes responsible for detecting and correcting
DNA base pair mismatches. A succinct and compelling description of a genetic
model for colorectal tumorigenesis has been published by Fearon and Vogelstein.[13]
These findings, and many
more like them, provide hope for an eventual understanding of the basic causes
of familial and sporadic colorectal cancer. However, to date, the basic understanding
of the molecular biology of colorectal cancer, the recognition of the role of
diet in the development of these cancers, the observation that several chemicals
(nonsteroidal anti-inflammatory drugs, antioxidants, vitamins, and calcium)
can prevent colorectal cancer or cause regression of its precursor adenoma,
the development of new screening strategies, the routine use of more aggressive
operations for primary tumors and metastases, and the aggressive administration
of adjuvant chemical therapy have produced neither a significant decrease in
the incidence of this disease nor an improvement in the chance of survival of
patients who are unfortunate enough to develop it.
Richard C. Karl, MD
Juan C. Bolivar Professor
of Surgical Oncology
H. Lee Moffitt Cancer Center
& Research Institute
Tampa, Florida
References
- Sugarbaker JP, Gunderson
LL, Wittes RE. Colorectal cancer. In: DeVita VT, Hellman S, Rosenberg SA,
eds. Cancer: Principles and Practice of Oncology. Philadelphia, Pa: J B Lippincott;
1985.
- Vargas PA, Alberts DS.
Primary prevention of colorectal cancer through dietary modification. Cancer.
1992;70(Suppl 5):1229-1235.
- Steele G. Natural history
and the evolution of regional treatment modalities for patients with isolated
liver metastases from primary colon and rectum carcinoma. Cancer Cont: J M
C C. 1996;3:34-41.
- Bos JL, Fearon ER, Hamilton
SR, et al. Prevalence of ras gene mutations in human colorectal cancers.
Nature. 1987;327:293-297.
- Forrester K, Almoguera
C, Han K, et al. Detection of high incidence of K-ras oncogenes during
human colon tumorigenesis. Nature. 1987;327:298-303.
- Jessup JM. Molecular
biology of neoplastic transformation of the large bowel. Surg Oncol Clin North
Am. 1994;3:449-477.
- Alitalo K, Schwab M,
Lin CC, et al. Homogeneously staining chromosomal regions contain amplified
copies of an abundantly expressed cellular oncogene (c-myc) in malignant
neuroendocrine cells from a human colon cancer. Proc Natl Acad Sci U S A.
1983;80:1707-1711.
- Erisman MD, Rothberg
PG, Diehl RE, et al. Deregulation of c-myc gene expression in human
colon carcinoma is not accompanied by amplification or rearrangement of the
gene. Mol Cell Biol. 1985;5:1969-1976.
- Vogelstein B, Fearon
ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development.
N Engl J Med. 1988;319:525-532.
- Delattre P, Olschwang
S, Law DJ, et al. Multiple genetic alterations in distal and proximal colorectal
cancer. Lancet. 1989;2: 353-356.
- Fearon ER, Hamilton SR,
Vogelstein B. Clonal analysis of human colorectal tumors. Science. 1987;238:193-197.
- Edelman GM. Morphoregulatory
molecules. Biochemistry. 1988;27:3533-3543.
- Fearon ER, Vogelstein
B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759-767.
Back
to Cancer Control Journal Volume 3 Number 1