Original ArticleExpression of Matrix Metalloproteinase-9, Pituitary Tumor Transforming Gene, High Mobility Group A 2, and Ki-67 in Adrenocorticotropic Hormone–Secreting Pituitary Tumors and Their Association with Tumor Recurrence
Introduction
Cushing disease (CD), caused by a pituitary corticotroph adenoma, comprises 70% of endogenous Cushing syndrome.1 In Cushing's original series, the mean duration from presentation to death was 4.7 years.2 In a recent multicenter, multinational, retrospective cohort study, compared with the general population, patients with CD who had been in remission for more than 10 years were at an increased risk of overall mortality, particularly from circulatory disease.3 Over the past 6 decades, even with advances in surgical techniques and medical treatment, CD remains associated with significant morbidity, especially metabolic and cardiovascular complications, osteoporosis, psychiatric changes, and cognitive impairment, as a result of chronic hypercortisolism.
Although transsphenoidal adenomectomy is the first treatment of choice, with immediate postoperative remission rates ranging between 65% and 90%, tumor recurrence rates are as high as 12%–45%, leading to a therapeutic challenge for endocrinologists and neurosurgeons.4, 5 The second line of therapy includes radiotherapy, bilateral adrenalectomy, and medical treatment.5 Specific medical therapies are categorized based on their mechanism of action: pituitary-directed (cabergoline and pasireotide), adrenal/steroidogenesis-directed (ketoconazole, metyrapone, and mitotane), and end-tissue–directed/cortisol receptors (mifepristone).6 Pasireotide, which was granted approval by the Food and Drug Administration for the treatment of CD in December 2012, is of particular utility in patients who are not eligible for surgery or patients with recurrence.7
Although some clinical predictive factors, such as postoperative serum cortisol levels and corticotropin-releasing hormone tests, have been studied systematically and may be associated with tumor recurrence status,8 few studies have investigated the association between biomarkers and the risk of recurrence of adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Therefore, it is important to identify effective biomarkers for predicting the proliferative potential and potential for recurrence of CD, with the aim of identifying CD recurrence early and initiating an appropriate follow-up and therapeutic protocol, thus avoiding long-term mortality.
Although the molecular mechanisms underlying the tumorigenesis and progression of ACTH-secreting pituitary tumors are still elusive, pituitary corticotroph adenomas are monoclonal.9 Recent studies have shown that USP8 is frequently mutated in CD and contributes to ACTH overproduction by enhancing the promoter activity of the proopiomelanocortin gene.10, 11 However, no biomarkers have been reliably associated with tumor behavior and the recurrence of CD.
A large number of studies have suggested that matrix metalloproteinase-9 (MMP-9), pituitary tumor transforming gene (PTTG), and high mobility group A 2 (HMGA2) play key roles in the development of pituitary adenomas. Human PTTG was initially isolated from pituitary tumor cells and identified as securin, which is a protein regulating chromosome separation. PTTG is abundantly expressed in pituitary tumors and is a biological marker of malignancy grades in several forms of tumors, particularly endocrine tumors such as pituitary adenomas.12 However, other studies have suggested that the expression of PTTG was not significantly associated with tumor invasiveness in patients with pituitary adenomas.13 Tumor-secreted matrix metalloproteinases degrade extracellular matrix, thus enabling tumor invasion. A previous study reported that MMP-9 may influence the invasiveness and recurrence of pituitary adenomas.14 HMGA2 is overexpressed in various benign and malignant tumors, is associated with a highly malignant phenotype, and is regarded as a poor prognostic indicator.15 Transgenic mice with overexpression HMGA2 develop pituitary adenomas that secrete prolactin and growth hormone, thus suggesting that HMGA2 may be involved in pituitary tumorigenesis.16
Whether MMP-9, PTTG, and HMGA2 are related to ACTH-secreting tumor recurrence is still unclear. In this study, we investigated the expression profile of MMP-9, PTTG, HMGA2, and Ki-67 in ACTH-secreting pituitary tumors and evaluated their association with tumor behavior and recurrence. Using this approach, we hope to identify molecular biomarkers to predict CD recurrence.
Section snippets
Patients and Samples
All procedures were approved by the Research Ethics Committee of Peking Union Medical College (Beijing, China), and informed written consent was obtained from all patients. A total of 550 patients were diagnosed with CD and underwent surgery at Peking Union Medical College Hospital, one of the earliest and largest pituitary centers in China, between 1990 and 2004. Approximately 60% of the patients were lost to follow-up. Of the approximately 220 patients with complete follow-up data, 55
Expression of PTTG and Its Association with the Clinicopathologic Characteristics of ACTH-Secreting Pituitary Tumors
IHC staining showed strong cytoplasmic and moderate nucleic PTTG immunoreactivity in 22 of 28 nonrecurrent tumors (79%) and in 21 of 27 recurrent tumors (78%) but no staining in the 2 normal pituitaries. Representative images of PTTG staining in ACTH-secreting pituitary tumors and in the normal pituitary glands are shown in Figure 1A. In the nonrecurrent group, the degree of immunostaining was 4+ in 5 cases, 3+ in 5 cases, 2+ in 2 cases, and 1+ in 10 cases, whereas in the recurrent group, the
Discussion
Until now, most of the studies investigating the factors that predict ACTH-secreting pituitary tumor recurrence have focused on clinical factors. These reports have identified several factors that are associated with hypercortisolism after transsphenoidal surgery or with greater recurrence rates, such as male sex, young age, invasive tumor, high postoperative serum cortisol levels, and perioperative plasma ACTH levels.18, 19
Because pituitary adenomas, including CD, arise from monoclonal growth
Conclusions
In our study, ACTH-secreting pituitary tumors with increased expression of MMP-9 were associated with recurrence and a shorter disease-free interval. Patients with high MMP-9 expression may need particularly close clinical and radiologic follow-up after surgery. Although further confirmatory studies are needed, MMP-9 may be a valuable tool for predicting the proliferative potential of pituitary tumors and may be useful for treatment planning and patient follow-up.
The major limitation of our
References (37)
- et al.
Mortality in patients with Cushing's disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study
Lancet Diabetes Endocrinol
(2016) - et al.
Cushing's syndrome
Lancet
(2015) - et al.
Pituitary tumor transforming gene causes aneuploidy and p53-dependent and p53-independent apoptosis
J Biol Chem
(2000) - et al.
Diagnosis and complications of Cushing’s syndrome: a consensus statement
J Clin Endocrinol Metab
(2003) The basophil adenomas of the pituitary body and their clinical manifestations
Bull Johns Hopkins Hosp
(1932)- et al.
Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement
J Clin Endocrinol Metab
(2008) - et al.
The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery
J Clin Endocrinol Metab
(2009) - et al.
Pasireotide for the treatment of Cushing's disease
Expert Opin Investig Drugs
(2010) - et al.
Long-term remission and recurrence rates in Cushing's disease: predictive factors in a single-centre study
Eur J Endocrinol
(2013) - et al.
Clonal origins of adrenocorticotropin-secreting pituitary tissue in Cushing’s disease
J Clin Endocrinol Metab
(1992)
Recurrent gain-of-function USP8 mutations in Cushing's disease
Cell Res
Mutations in the deubiquitinase gene USP8 cause Cushing's disease
Nat Genet
Isolation and characterization of a pituitary tumor transforming gene (PTTG)
Mol Endocrinol
A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors
Endocr Relat Cancer
Role of matrix metalloproteinase 9 in pituitary tumor behavior
J Clin Endocrinol Metab
Roles of HMGA proteins in cancer
Nat Rev Cancer
Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas
Oncogene
Differential expression of folate receptor alpha in pituitary adenomas and its relationship to tumor behavior
Neurosurgery
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Conflict of interest statement: Financial support for this study was provided by the National Natural Science Foundation of China (grant number: 81501192), the National Science & Technology Pillar Program during the 12th Five-year Plan Period (grant number: BAIO4B03), and the Youth Scientific Research Fund in Peking Union Medical College Hospital (pumch-2016–2.20). The funding institutions had no role in the design of the study, data collection and analysis, the decision to publish, or the preparation of the manuscript.
Xiaohai Liu and Ming Feng contributed equally to this work.