Abstract

The increased invasiveness of colorectal cancer cells is important for progression and metastasis to the surrounding organs. According to recent molecular biological studies, signaling through transmembrane Prokineticin-Receptor2(PK-R2) is likely involved in the ability of tumor cell to invade. However, no studies have evaluated the relationship between PK-R2 expression, ability of cancer to invade/metastasize, and patient prognosis in cases of resected colorectal cancer. Accordingly, we have examined these factors in the present study.Immunohistochemical staining was performed to detect PK-R2 in the primary lesion and adjacent normal large intestine mucosa of 324 colorectal cancer patients who underwent resection surgery at our department. Additionally, we conducted clinicopathologic examinations and analyzed patient prognoses with the Kaplan-Meier method. Further, multivariate analysis was conducted using a cox-proportional hazard model.PK-R2 expression was observed on the cellular membrane of the primary lesion in 147 of 324 cases (45.3%) of human colorectal cancer. PK-R2 expression was associated with a higher incidence of vascular invasion, lymph node metastasis, hepatic metastasis, and hematogenous metastasis. Further, prevalence of PK-R2 expression increased as tumor stage increased. In stage III curative resection cases, where recurrence is the most serious problem, cases that expressed PK-R2 had a significantly lower 5-year survival rate (82.1% versus 66.8%) and higher recurrence compared to those cases with no PK-R2 expression. In the multivariate analysis for prognosis, PK-R2 expression was found to be an independent factor(ratio2.621).PK-R2 expression could be one of the new prognostic factors in human colorectal cancer.

Highlights

  • Colorectal cancer has one of the highest prevalence and mortality rates among malignant tumors [1,2,3,4]

  • While PK-R2 expression was not observed in the healthy mucosal membrane adjacent to human colorectal cancer, its expression was found in the primary lesion of colorectal cancer

  • PROK1 was found to be strongly expressed in a number of malignant tumors including prostate cancer, neuroblastoma, pancreatic duct cancer, thyroid cancer, and colorectal cancer, and a relationship with the level of malignancy was confirmed [25,26,27,28,29,30,31,32]

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Summary

Introduction

Colorectal cancer has one of the highest prevalence and mortality rates among malignant tumors [1,2,3,4]. One model for the mechanism of hematogenous metastasis of colorectal cancer involves growth of tumor at the primary lesion, dissociation of cancer cells, invasion into interstitium, invasion into blood vessels, and implantation and growth in the liver and other distant organs. The invasiveness of colorectal cancer is influenced by the interaction between the cell surface proteins of the tumor cell and the extracellular matrix. Proteases such as matrix metalloprotease (MMP) break down the extracellular matrix to allow the tumor cell to pass through the base membrane and penetrate the inside of the tissue [11, 12]. The involvement of the Rho GTPase family in this mechanism has been observed, and drugs targeting these proteins have recently been developed [19, 20]

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