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Editorial |
Department of Medicine (S.R.B.), University of Dresden, D-01307 Dresden, Germany; and Department of Physiology and Sam and Ann Barshop Institute for Longevity and Aging Studies (P.J.H.), University of Texas Health Science Center, San Antonio, Texas 78245
Address all correspondence and requests for reprints to: Stefan R. Bornstein, M.D., PhD., Professor of Medicine, Director and Chair, Endocrinology, Diabetes and Metabolism, Department of Medicine, Carl Gustav Carus University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany. E-mail: stefan.bornstein{at}uniklinikum-dresden.de.
Adrenal cancer is one of the malignancies in humans that is detected late and has an extremely poor prognosis, with no effective treatment option in the advanced stages (1). Fortunately, it is a rare malignancy, with an incidence of one to four cases per million people. This contrasts with the fact that benign adrenal lesions are among the most common tumors in humans (2). Clinically inapparent adrenal masses are frequently discovered incidentally ("incidentalomas") by ultrasound, computed tomography, or magnetic resonance imaging, performed for reasons not related to endocrine disease. The dilemma for clinicians, therefore, is how to rule out malignant causes for adrenal imaging findings, and then whether to monitor or treat the lesions at all, either surgically or medically. Currently this decision process is hindered by a lack of knowledge of the pathogenesis of adrenal tumors and of molecular markers that could assist definitive diagnosis by fine needle biopsy. Furthermore, histopathological criteria, immunohistochemical markers, and hormonal and chromosomal analyses have thus far not delivered a reliable algorithm to differentiate benign lesions from malignant ones or to predict prognosis or the likelihood of recurrence (1, 2, 3).
A recent National Institutes of Health State-of-the-Science conference on adrenal incidentaloma and an international consensus conference on adrenal cancer held in Ann Arbor (Michigan) stressed the need to identify reliable markers for the clinical management of adrenal tumors. The paper by de Fraipont et al. (4) in the current issue of the JCEM approaches this need by employing gene expression profiling using microarrays, a technique successfully used previously in breast cancer and lymphoma to identify potential genes as markers of malignancy (5, 6, 7). This group has established a nationwide network in France for studies on human adrenal tumors, providing an ideal resource to analyze a rare disease such as adrenal cancer in an appropriate set of samples. They have designed an adrenal-specific microarray ("adrenochip") comprising 34 adrenocortical-specific genes in addition to 17 cancer-related genes, all of known biological function (4).
Using this approach, they identified two clusters of genes (the IGF2 cluster containing eight genes, including IGF2, and the steroidogenesis cluster containing six genes encoding steroidogenic enzymes, plus eight other genes). Used in combination, the expression levels of these two clusters provided a good predictor of malignancy. This predictive value was as strong as that of the pathological score of Weiss. An analysis of the population of carcinomas (13 tumors) allowed the identification of 14 genes whose expression differed strongly between recurring and nonrecurring tumors (4).
This study nicely confirmed an earlier DNA microarray analysis by Giordano et al. (8) of 10,000 genes, as well as previous expression studies in a smaller set of samples demonstrating up-regulation of various growth factors, particularly IGF2 (9). Therefore, there is now extensive evidence demonstrating that increased IGF2 expression is highly characteristic of transcriptional changes in adrenocortical cancer (8). These data suggest that signal transduction in response to IGF2 may constitute a promising therapeutic target for this tumor.
Interestingly, the microarray studies also identified novel differentially expressed genes, such as osteopontin, which was previously identified as a potential serum marker for ovarian cancer (10).
The analysis of 14 genes related to steroidogenesis is of particular interest, as it pursues a concept of great potential for endocrine and endocrine-related tumors. Hormonal dysregulation and impairment of hormone biosynthetic pathways have been demonstrated in various endocrine tumors, including adrenal cancer, and a correlation of endocrine function tests together with expression profiling may eventually lead to a clinical algorithm allowing the definition of the dignity and prognosis of an endocrine tumor. Another exciting finding revealed by the gene array studies is the differential regulation of immune-related genes that may be significant for the prognosis of adrenal cancer. In particular, genes implicated in the innate immune response and cell-cell contacts such as integrins and granzyme B are differentially expressed (4). This is in accordance with recent results demonstrating differential regulation of these genes by glucocorticoids and a newly discovered role for Toll-like receptors and chemokines in the adrenal and/or adrenal cancer (11, 12, 13). Despite the evidence that immune effectors can play a very important role in controlling tumor growth in natural conditions or in response to therapeutic manipulation, it is evident that cancer cells can survive their assault as the disease progresses. Various mechanisms underlying immune escape have been suggested, such as down-regulation of human leukocyte antigen molecules/tumor-associated antigen on tumor cell surface, the production of immunosuppressive cytokines, and the expression of lymphotoxic molecules by malignant cells (14).
A distinctive feature of malignant adrenocortical neoplasms is decreased major histocompatibility class II expression. The major histocompatibility class II genotype and phenotype and the altered FAS/FAS ligand system in adrenal neoplasms may help to identify mechanisms of immune escape (15). Therefore, considering the complexity of an immune-adrenal network, high-throughput DNA array analysis based on new insights from cancer immunogenomics may provide promising avenues for the treatment of this dismal disease (14).
In addition to the genes confirmed or newly discovered by these microarray studies, three other factors related to cell growth and metabolism have recently been shown to be associated with malignancy or unfavourable outcome in adrenal tumors. First, in a study conducted in Brazil (16), the GATA transcription factors, which play an essential role in the control of development, cell proliferation, and cell differentiation, were shown to be differentially expressed during adrenal tumorigenesis. In particular, GATA 4 was more abundant in mestastasizing/recurrent adrenocortical neoplasms (16). Second, in a report performed partly by the same authors as the microarray analysis (17), cyclin E was found to correlate with malignancy and adverse prognosis in adrenocortical tumors. Cyclin E overproduction was associated with the malignant phenotype and was strongly correlated with tumor size, Weiss score, the presence of genetic abnormalities such as loss of heterozygosity at 17p13, and overexpression of the IGF2 gene (18). Third, decreased expression of cAMP-regulated aldose reductase (AKR1B1) was suggested to be associated with malignancy in human sporadic adrenocortical tumors (17). The human aldose reductase AKR1B1 participates in glucose metabolism and plays a protective role against toxic aldehydes derived from lipid peroxidation and steroidogenesis that could affect cell growth. Interestingly, most adrenocortical carcinomas had very low AKR1B1 protein levels when compared with benign tumors, suggesting that this protein may be another useful marker of malignancy for future diagnosis of adrenal tumors (17).
In summary, microarray analysis has the potential to significantly impact our ability to elucidate mechanisms of adrenal tumorigenesis, to provide biomarkers for disease diagnosis and prognosis, and to help the design of new therapeutic strategies (5, 6). However, more validation of the analysis by mRNA levels, fluorescence-activated cell sorting, Western blotting, and hormone levels in combination with tissue arrays will be helpful to provide reliable and consistent results (7). Another important requirement to improve the results is more standardization and definition of the tumor samples used for analysis. One approach is to combine microarray analysis with procurement of adrenal tumor cells by laser capture microdissection (19).
Despite the high level of genetic instability found in benign adrenal lesions, conclusive evidence for later malignant transformation in these tumors is hard to obtain (20). Therefore, identifying the genetic mechanisms that enable a small minority of tumors to acquire fully malignant properties will be of great interest not only for adrenal carcinogenesis but for the entire field of endocrine oncology. Novel genomic and proteomic techniques, such as high-resolution genome-wide array comparative genome profiling and protein-detecting arrays, are now available and offer new opportunities to investigate adrenal tumorigenesis. The discoveries that come from these techniques must be validated by directly demonstrating that these genes can cause the transformation of normal human adrenocortical cells to benign or malignant tumors, for example by employing a xenograft model in immunodeficient mice (21).
Received January 12, 2005.
Accepted January 17, 2005.
References
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  A. Horvath, L. Mathyakina, Q. Vong, V. Baxendale, A. L. Y. Pang, W.-Y. Chan, and C. A. Stratakis Serial Analysis of Gene Expression in Adrenocortical Hyperplasia Caused by a Germline PRKAR1A Mutation J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 584 - 596. [Abstract] [Full Text] [PDF]
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M. H. Bassett, B. Mayhew, K. Rehman, P. C. White, F. Mantero, G. Arnaldi, P. M. Stewart, I. Bujalska, and W. E. Rainey Expression Profiles for Steroidogenic Enzymes in Adrenocortical Disease J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5446 - 5455. [Abstract] [Full Text] [PDF]
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