© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 17, 1281,
September 5, 2001
© 2001 Oxford University Press
IN THIS ISSUE |
Microsatellite instability (MSI) is seen in 10%–15% of sporadic colorectal cancers mostly in the right colon, but the precursors of cancers with MSI remain unknown. Hawkins and Ward (p. 1307) examined whether sporadic cancers with MSI arise from pre-existing benign proliferative lesions such as hyperplastic polyps or serrated adenomas, together denoted as serrated polyps. They examined the frequency of synchronous serrated polyps in individuals with colorectal cancer, as well as the MSI status, expression of mismatch repair enzyme (product of the hMLH1 gene), and hMLH1 gene promoter methylation in the benign lesions. Individuals with cancers showing MSI were more likely to harbor at least one serrated polyp than individuals with cancers showing microsatellite stability (MSS). Loss of hMLH1 protein expression and hMLH1 promoter methylation were observed in serrated polyps from some patients with MSI but not in patients with cancers with MSS. The authors conclude that hyperplastic polyps may progress to sporadic colorectal carcinomas with MSI and that methylation of the hMLH1 gene promoter may play a critical role in this progression.
In an editorial, Hamilton (p. 1282) points out that, although the absolute and relative risks of colon cancer in patients with these lesions are unknown, the study by Hawkins and Ward provides a model for studying progression of hyperplastic polyps to colon cancer. Hamilton also notes that the implications of their findings for patient management are uncertain.
"Prospective studies are needed to determine the real risk of malignant progression in these lesions and the most effective way of identifying those particular hyperplastic polyps with malignant potential."
—Hawkins and Ward
HPV16 Variants and Risk for Cervical Cancer
Human papillomavirus 16 (HPV16) has many variants, which are distributed differently throughout the world. Some HPV16 variants are more often associated with invasive cervical cancers. To investigate the high incidence of cervical cancer in Mexico, Berumen et al. (p. 1325) conducted a case–control study in Mexico City to identify HPV16 variants and determine whether certain variants were associated with an increased risk of cervical cancer. They detected HPV16 in about half of the cervical cancers tested and in about 10% of the control samples; all but one sample contained European (E) or Asian-American (AA) variants. The frequency of AA variants was 21 times higher in cancer patients than in control subjects, whereas the frequency of E variants was only 2.7 times higher. The authors conclude that the high frequency of HPV16 AA variants, which may be more oncogenic than E variants, might contribute to the high incidence of cervical cancer in Mexico.
"In addition to HPV types, the prevalence of HPV variants should be considered when designing the appropriate HPV vaccine for a specific area."
—Berumen et al.
Delivery of Adenoviral-Bax to Prostate Cancer Cells
Adenoviral constructs are efficient vectors for introducing genes into tumor cells but may have unwanted side effects by expression in cells other than the target cells. Andriani et al. (p. 1314) have developed an adenoviral vector to introduce the gene for Bax, an apoptosis-inducing protein, specifically into prostate cancer cells. To ensure that Bax was expressed only in prostate cancer cells, the authors used the promoter of a prostate-specific gene, probasin, with two androgen response elements. The resulting vector, Av-ARR2PB-Bax, expressed Bax only in androgen receptor (AR)-positive cells of prostatic origin but not in AR-positive cells of non-prostatic origin or in AR-negative cells of any origin. Injection of Av-ARR2PB-Bax into AR-positive prostate cancer tumor xenografts resulted in an increase in the percentage of apoptotic cells and a decrease in tumor size. The authors conclude that Av-ARR2PB-Bax is an efficient vector for inducing androgen-dependent therapeutic apoptosis specifically in AR-positive prostatic cells.
Dairy Products and Colorectal Cancer Risk
Dairy products have potentially opposing effects on colorectal cancer: Whereas dietary calcium appears to reduce colorectal cell proliferation, milk intake may raise serum levels of insulin-like growth factor-I (IGF-I). IGF-I is a potent stimulator of cell division, and individuals with a high ratio of IGF-I to IGF-binding protein-3 (IGFBP-3) appear to be at increased risk of colorectal cancer. In this issue, Ma et al. (p. 1330) report that, in a case–control study nested in the prospective Physicians’ Health Study, intake of dairy products was indeed associated with a modest increase in circulating IGF-I levels. However, intake of low-fat milk was also associated with a reduced risk of colorectal cancer, especially among men with a high ratio of IGF-I to IGFBP-3. The authors suggest that individuals with a high IGF-I/IGFBP-3 ratio—who are at the highest risk of colorectal cancer—may benefit most from the intake of dietary calcium.
Genes Transcribed in Response to Tumor Hypoxia
Tumor growth is associated with the development of regions within the tumor that are starved of oxygen; tumors adapt to this state by generating a blood supply, a process called angiogenesis, which appears to involve altering gene expression in hypoxic cells. Lal et al. (p. 1337), using glioblastoma cells, examined RNA transcripts produced in response to oxygen deprivation. They identified 10 genes with varied functions that were expressed at higher levels than vascular endothelial growth factor, a protein involved in tumor blood vessel growth. These same genes were also found to be expressed in breast cancer and colon cancer cells. In addition, the genes were activated by hypoxia-inducible factor 1, a key regulator of cellular response to hypoxia. The authors conclude that these genes may play a role in hypoxia-driven angiogenesis.
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