Correspondence to: Frances Balkwill, Ph.D., Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London, WC2A 3PX U.K.
In the September 1, 1999, issue of the Journal, Ness and Cottreau (1) discuss the role of inflammation in the pathogenesis of ovarian cancer. In reviewing the current literature, they conclude that neither incessant ovulation nor gonadotropin stimulation provides a completely satisfactory explanation for the genesis of ovarian cancer. They suggest that ovarian inflammation, with rapid DNA turnover, oxidative stress, and increased cytokine production, may be an important contributor to the development of ovarian malignancies.
For the past 10 years, we have been studying the role of cytokines in human ovarian cancer
biology. We have found that the cytokine network in this tumor is rich in proinflammatory
cytokines, growth factors, and chemokines (2-4). Our experiments to date
suggest that the proinflammatory cytokine tumour necrosis factor- (TNF-
) is central to
this ovarian cancer microenvironment. TNF-
is expressed in the epithelial tumor islands of
ovarian cancer biopsy specimens (the level of expression increasing with tumor grade) and is
implicated in the process of ovarian cancer stromal development and regulation of chemokines
and matrix metalloproteases [(2-6) and references therein].
We also carried out tumor induction experiments in TNF-
deficient mice and found that
these mice are resistant to skin carcinogenesis (7). This result provides
direct evidence that a proinflammatory cytokine is required for de novo carcinogenesis
and that TNF-
is important to the early stages of epithelial tumor promotion.
The role of TNF- in promoting the development of tumor stroma and controlling host
and tumor interactions appears to be analogous to its action in inflammatory disease. At some
stages of inflammation, TNF-
can cause tissue destruction and necrosis. Similarly, high
doses of TNF-
delivered locally to the tumor site cause disruption of the tumor vasculature
followed by necrosis. However, lower doses of endogenous TNF-
in the inflammatory
microenvironment can promote tissue repair via induction of chemokines and stimulation of
fibroblasts and neovasculature. The actions of endogenous TNF-
in cancer are similar,
except that TNF-
produced chronically in the tumor does not lead to resolution of the
lesion.
Thus, inflammatory cytokines in the tumor microenvironment may not contribute to the genetic damage that initiates the cancer but they may be "a fuel that fans the flames."
Finally, it is possible that inflammatory cytokines are important to the evolution of many different malignancies and not just epithelial ovarian cancer.
REFERENCES
1
Ness RB, Cottreau C. Possible role of ovarian epithelial
inflammation in ovarian cancer. J Natl Cancer Inst 1999;91:1459-67.
2 Naylor MS, Stamp GW, Foulkes WD, Eccles D, Balkwill FR. Tumor necrosis factor and its receptors in human ovarian cancer. Potential role in disease progression. J Clin Invest 1993;91:2194-206.[Medline]
3 Negus RP, Stamp GW, Relf MG, Burke F, Malik ST, Bernasconi S, et al. The detection and localisation of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer. J Clin Invest 1995;95:2391-6.[Medline]
4 Burke F, Relf M, Negus R, Balkwill F. A cytokine profile of normal and malignant ovary. Cytokine 1996;8:579-85.
5 Negus RP, Stamp GW, Hadley J, Balkwill FR. Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of c-c chemokines. Am J Pathol 1997;150:1723-34.[Abstract]
6
Leber TM, Balkwill FR. Regulation of monocyte MMP-9
production by TNF- and a tumor-derived soluble factor (MMPSF). Br J Cancer 1998;78:724-33.[Medline]
7 Moore R, Owens, D, Stamp, G, Arnott C, Burke F, East N, et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 1999;5:828-31.[Medline]
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