Downregulation of osteoprotegerin expression in metastatic colorectal carcinoma predicts recurrent metastasis and poor prognosis

Abstract

We recently reported the downregulation of osteoprotegerin expression in primary colorectal carcinoma and its significant association with aggressive oncogenic behavior, which suggest that this process contributes to colorectal carcinoma development and progression. In this study, we used immunohistochemical staining to evaluate osteoprotegerin expression in 81 colorectal liver metastasis tissue samples and investigated its possible association with the clinicopathological characteristics and outcomes of patients with colorectal liver metastasis. These tissues exhibited significantly reduced expression of osteoprotegerin compared to primary colorectal carcinomas and normal colorectal mucosa. This reduced expression was significantly associated with the extent of colorectal liver metastasis, including multiplicity of metastatic tumors, involvement of the bilateral hepatic lobes, and higher histological grade. In addition, reduced osteoprotegerin expression was an independent significant predictor of recurrent liver metastasis and prognostic factor for reduced patient survival. These findings suggest that osteoprotegerin expression may be a novel predictor of recurrent liver metastasis and a prognostic biomarker in patients with colorectal liver metastasis. Patients harboring colorectal liver metastasis with reduced osteoprotegerin expression should be carefully monitored after hepatic resection for colorectal liver metastasis to enable early detection of potentially resectable metastatic recurrences.

Down-regulation of Inositol Polyphosphate 4-Phosphatase Type II Expression in Colorectal Carcinoma

“…Two independent Board-certified pathologists reviewed all hematoxylin and eosin-stained slides and selected the most representative slide from each case for immunohistochemical staining. The 81 patients in this study met the following criteria for hepatic resection with curative intent; medical fitness for major hepatic resection; colorectal liver metastasis that resulted in adequately sized, well-vascularized hepatic remnants after hepatic resection; and no signs of extrahepatic metastases in preoperative imaging studies, including chest radiography, abdominal ultrasonography, abdominopelvic computed tomography, and pelvic magnetic resonance imaging (3,5,25,26). No patient underwent preoperative neoadjuvant chemotherapy or neoadjuvant concurrent chemoradiation therapy.…”

“…Despite the availability of preventive screening, colorectal carcinoma (CRC) remains one of the most commonly diagnosed malignancies, even in the developed world. It is the fourth most common cancer in Western countries and second leading cause of cancer-related deaths in Europe and North America (1)(2)(3). In the Republic of Korea, CRC is the third most common cancer and fourth leading cause of cancer-related deaths (4).…”

“…Identifying patients at high risk of recurrence or metastasis conventionally depends on clinical and pathological parameters, such as tumor stage, invasion depth, mural perforation or invasion of adjacent organs, and metastasis to regional lymph nodes or distant organs. However, the current staging system is limited in that it cannot offer a prognosis for individual patients (3,5). In order to improve the outcomes of patients with CRC, it is crucial to identify cancer-related genes that can serve as diagnostic or predictive biomarkers for individualize therapy.…”

“…In CRC, activation of the phosphatidylinositol 3-kinase (PI3K) pathway is particularly important because many common genetic and epigenetic abnormalities in the disease, such as amplification of epidermal growth factor receptor, activating mutations of Kirsten ras proto-oncogene (KRAS), GTPase, and loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), converge to activate PI3K signaling (9,10). Binding of extracellular growth factors to receptor tyrosine kinases results in the recruitment of PI3K to plasma membrane-anchored receptors where it is activated, leading to increased production of phosphatidylinositol 3,4bisphosphate and phosphatidylinositol 3,4,5-trisphosphate [PI (3,4,5)P3], which in turn bind to and activate multiple downstream effectors (6,11,12). Among them, AKR mouse thymoma kinase (AKT) is activated by two phosphorylation events at Thr308 and Ser473 involving phosphoinositidedependent kinase 1 and the mammalian target of rapamycin complex 2, respectively (13,14).…”

“…Activation of PI3K signaling is negatively regulated by three classes of inositol polyphosphate phosphatases (16)(17)(18)(19)(20)(21). PTEN dephosphorylates the 3-position of PI (3,4,5)P3 to generate PI(4,5)P2, whereas 5-phosphatases, such as v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene (SRC) homology 2 domain-containing inositol 5-phosphatase and PI(4,5)P2 5-phosphatase A/proline-rich inositol polyphosphate phosphatase, dephosphorylate the 5-position of PI (3,4,5)P3 to produce PI (3,4)P2. The latter is in turn subjected to dephosphorylation by inositol polyphosphate 4phosphatase type I and type II (INPP4B) at the 4-position to generate PI(3)P, thus terminating PI3K signaling (16,22).…”