Affiliations of authors: R. Bos, P. J. van Diest (Department of Pathology), E. van der Wall (Department of Medical Oncology), Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
Correspondence to: Elsken van der Wall, M.D., Ph.D., Department of Medical Oncology, Vrije Universiteit Medical Center, P.O. Box 7057, NL-1007 MB, Amsterdam, The Netherlands (e-mail: e.vanderwall{at}vumc.nl).
Uncontrolled cellular proliferation will inevitably lead to a tumor mass, with an increased distance between tumor cells and the vascular system resulting in hypoxia
(1).
This hypoxia often stimulates the synthesis of hypoxia-inducible factor-1 (HIF-1
), a key regulator of cancer-associated processes, such as angiogenesis and the Warburg effect, increasing cellular survival. HIF-1
may, therefore, be involved in carcinogenesis or progression of many solid tumors, as described for the breast
(2)
and prostate
(3).
The results by Costa et al. suggest that this hypothesis may also hold for oral cavity cancer.
There are, however, some reasons for caution regarding their study and some differences with our breast study. In their progression model, two types of preinvasive lesions of the oral cavity are included, without stratifying for grade of dysplasia. Leukoplakia is a clinical rather than a histologic entity, and the preinvasive nature of lichen planus is controversial, as the authors indicate. Assessment of dysplasia is, therefore, essential for the identification of preinvasive lesions; one would expect the HIF-1-positive preinvasive lesion and resection margin to be dysplastic. The HIF-1
positivity in normal mucosa adjacent to cancer is interesting. We have made similar observations in the breast, which can be regarded as a malignancy-associated change. These observations underline the importance of obtaining control tissue from healthy control subjects.
Costa et al. further report that HIF-1 positivity was noted in well-differentiated rather than poorly differentiated lesions, contrary to our results in the breast. According to our own calculations, the differences described by Costa et al. do not achieve statistical significance (
2
test). It would indeed be counterintuitive to find more HIF-1
in well-differentiated lesions, especially in view of the fact that HIF-1
was especially noted around necrotic areas that generally occur more frequently in poorly differentiated lesions. Thus, it is interesting to note the negative association between HIF-1
positivity and the apoptotic rate that is described. We have reanalyzed the apoptotic rate of the cancers from our initial breast study as described previously
(4)
and found that HIF-1
was strongly positively associated with the apoptotic rate (P = .002;
2
test). This observation is no surprise because we know that the apoptotic rate increases during breast carcinogenesis
(5)
and is high in highly proliferative and poorly differentiated cancers
(6).
The authors provide no explanation for their intriguing and counterintuitive observation. An explanation for the opposite (as in the breast) can be found in the fact that hypoxia inhibits Bcl-2, which has an antiapoptotic effect, via HIF-1
(5).
Some of these counterintuitive observations could be caused by the relatively low number of case patients studied or point to a differential carcinogenetic role of HIF-1 in different types of tissues. Nevertheless, the study by Costa et al. confirms the hypothesis that HIF-1
activity may play an important role in the carcinogenesis and progression of different types of solid human cancers. We thus believe that further tissuebased studies and the development of HIF-1
-targeting therapeutics
(7)
are required.
NOTES
Supported by the AEGON International Scholarship in Oncology (to R. Bos).
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