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Editorial |
Department of Orthopaedic Surgery Center for Orthopaedic Research University of Arkansas for Medical Sciences Little Rock, Arkansas 72205
Address all correspondence and requests for reprints to: Larry J. Suva, Department of Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansas 72205. E-mail: SuvaLarryJ{at}uams.edu.
It was Albright (1) who first proposed that humoral factors produced by cancer cells act on bone and kidney to increase bone resorption and impair calcium excretion. PTH was initially implicated as the hypercalcemic agent. However, after the identification and cloning of PTHrP (2), subsequent studies demonstrated a pivotal role for this molecule, and not PTH, as the primary mediator of tumor-induced hypercalcemia. More recently, the once well-accepted and central role of PTHrP in mediating the process of breast cancer metastasis to bone has been questioned (3, 4).
In contrast to the ubiquitous expression of PTHrP, the ectopic expression of PTH by tumor cells is very rare (5, 6, 7) and has been described as the cause of the hypercalcemia associated with malignancy that occurs in the absence of osteolytic bone metastases. Currently, there are several cases of ectopic PTH secretion reported in the literature, with only a handful documenting tumor cell expression of the PTH gene (8, 9, 10). In general, all of these examples documented molecular rearrangements of the PTH gene as the cause of the ectopic expression.
It is well accepted that the cause of primary or secondary hyperparathyroidism is the overproduction of PTH by neoplastic or hyperplastic parathyroid tissue (11). During renal failure, the gradual loss of kidney function is often accompanied by increased circulating PTH and decreased 1,25-dihydroxyvitamin D3 levels. The decreased 1,25-dihydroxyvitamin D3 results in impaired calcium absorption and the lowering of serum calcium, a known repressor of PTH gene transcription.
Studies of the molecular rearrangements of the PTH gene have revealed important information regarding the excessive parathyroid cell proliferation causally associated with increased PTH secretion of hyperparathyroidism. The properties of neoplastic proliferation and hormonal dysregulation appear tightly linked (12). However, whether abnormal parathyroid proliferation is the cause or result of a shift in calcium-sensitive parathyroid hormonal regulation remains controversial. It has been demonstrated that overexpression of the cyclin D1 oncogene can cause both the parathyroid hypercellularity and abnormal control of hormonal secretion that are almost inevitably linked together (13). However, these observations do not explain the specificity of PTH gene expression by the parathyroid.
Many transcription factors (Tbx1, Hoxa3, Pax1, Pax9, Eya1, GCMB) (14) have been shown to play a role in the development of the normal parathyroid gland. Still other specific factors (Sp1, Sp3, NFY
, NFYß, and NFY
) have been shown to bind to and modulate the PTH gene promoter in vitro (15). Several of these transcription factors play a critical role in PTH secretion, and mutations in the GCMB transcription factor have been implicated in syndromes of hypoparathyroidism (16, 17).
Interestingly, although the absence of one of these transcription factors (Gcm2) in mice leads to the lack of parathyroid glands, the mice continue to have detectable serum PTH levels (18). However, although a subset of cells in the mouse thymus exist that coexpress a number of genes including PTH, and thereby serve as an auxiliary source of PTH (18), this is clearly not the case in humans (14). It appears that the elevated serum PTH without evidence of a parathyroid mass in this study is due to the ectopic expression of PTH by tumor cells (14).
The steady-state expression of the PTH gene should be considered a balance between transcriptional activators and repressors. Despite this level of understanding, the mechanism(s) for how these (or other) factors specifically restrict the expression of the PTH gene to parathyroid cells is unknown. Overall, although the role of PTH in the regulation of normal systemic calcium homeostasis is well known, the details of the regulation of PTH gene expression remain largely underexplored. This may be due, in part, to the lack of suitable cell models.
Against this backdrop is the important study of VanHouten et al. (19), in which the authors report a case of severe hyperparathyroidism resulting from the ectopic production of PTH (and PTHrP) by a high-grade, metastatic neuroendocrine carcinoma of the pancreas. Importantly, cells from the primary tumor were isolated and established in culture (so-called PEPP1 cells). These cells were then used as a model to examine in detail the specificity of PTH gene expression.
In contrast to previous studies investigating the molecular etiology of PTH gene expression in ovarian carcinoma (8), no evidence for amplification or rearrangements in the PTH gene were identified in the study by VanHouten et al. (19). These investigators (19) developed several lines of evidence to establish that PEPP1 cells express a normal PTH gene. Ectopic PTH expression was confirmed by quantitative PCR, ELISA, and immunohistochemistry, and the normal diploid karyotype of the cells was demonstrated. Also, no alterations in the regulatory sequences in the proximal promoter were identified. In addition, all the transcription factors previously implicated in parathyroid gland development and/or binding to the PTH promoter were unable to explain the selective activation of the gene in PEPP1 cells. Hypomethylation of the PTH promoter within the tumor was identified but not in the surrounding normal tissue. As previously described (20), hypomethylation of the PTH gene is unique to parathyroid tissue and, in this case, is likely indicative of active PTH gene transcription by the tumor. Further investigation using PEPP1 cells may provide new information regarding hypomethylation of the PTH gene in normal parathyroid gland, as well as shed light on the mechanism(s) responsible for ectopic PTH secretion by tumor tissue.
The finding of a normal PTH gene sequence, hypomethylation, and the lack of involvement of all known transcriptional regulators suggests that other, as-yet-unidentified, regulatory molecules are involved in the normal regulation and specificity of PTH gene expression. In support of this scenario, transfection of a 5.5-kb fragment of the human PTH promoter fused to a green fluorescent protein reporter gene into PEPP1 cells revealed strong basal transcription that was specific to PEPP1 cells. These observations raise the interesting possibility that PEPP1 cells recapitulate critical aspects of the regulatory environment of parathyroid cells, including the expression and regulation of a normal PTH gene.
Given the specificity of the control of normal PTH secretion, it is anticipated that continued investigation using the PEPP1 cell model will reveal the molecular details underlying the etiology of PTH gene expression. The elucidation of such pathways may provide novel insights into the treatment of disorders associated with increased PTH secretion via the modulation of the specific transcriptional regulators.
Received November 21, 2005.
Accepted December 2, 2005.
References
This article has been cited by other articles:
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  G. G. Schwartz Prostate Cancer, Serum Parathyroid Hormone, and the Progression of Skeletal Metastases Cancer Epidemiol. Biomarkers Prev., March 1, 2008; 17(3): 478 - 483. [Abstract] [Full Text] [PDF]
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