Soluble CD155 As A Biomarker For Malignant Bone And Soft Tissue Tumors

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1 Soluble CD155 As A Biomarker For Malignant Bone And Soft Tissue Tumors Mikinobu Goto, MD, Akihiko Matsumine, MD,PhD, Tomoki Nakamura, MD PhD, Takao Matsubara, MD PhD, Kunihiro Asanuma, MD,PhD, Toru Oi, MD, Akihiro Sudo, MD PhD. Mie university, Tsu, Japan. Disclosures: M. Goto: None. A. Matsumine: None. T. Nakamura: None. T. Matsubara: None. K. Asanuma: None. T. Oi: None. A. Sudo: None. Introduction: CD155 is an adhesion molecules which is named nectin like molecule-5 (NECL-5) belonging to an immunoglobulin superfamily, and is known also as a poliovirus receptor. It was previously reported that CD155 play an important role for cell adherence and movement, and is overexpressed at the leading edge of tumor cells.(1)(2) We have previously shown that CD155 was widely expressed in various type of human sarcoma cell lines and a high CD155 expression level was an independent adverse prognostic factor for local recurrence-free survival.(3) Recently, the presence of soluble CD155 (scd155) isoforms in culture medium conditioned by CD155-expressing cells and in human serum is reported. The aims of this study are to investigate the serum scd155 levels in patients with malignant bone and soft tissue tumors, and to evaluate the prognostic significance of the scd155 levels. Methods: Patient selection Serum samples were collected from 20 healthy subjects, 86 bone and soft tissue tumor patients,and 4 metastatic cancer patients with musculoskeletal metastases. The details of the clinicopathological features of 86 patients of the bone and soft tissue tumor are listed in Table 1. The mean follow-up period was 52 months (range, months). A mean age was 51 years (range,10-85 years) at the first presentation. The pathological diagnosis of 28 patients of malignant bone tumors were 16 osteosarcomas (OS), 5 chondrosarcomas(cs), 3 Ewing sarcomas(ews), and 3 chordomas, and a malignant fibrous histiocytoma of bone(mfh), respectively. All of three benign bone tumors were giant cell tumors (GCT). The pathological diagnosis of 48 patients of malignant soft tissue tumors were 10 malignant fibrous histiocytomas (MFH), 10 liposarcomas (LPS), 8 malignant peripheral nerve sheath tumors (MPNST), 3 dermatofibrosarcoma protuberans(dfsp), 3 leiomyosarcoma(lms), 3 myxofibrosarcoma(mfs), 2 synovial sarcomas, a rhabdomyosarcoma, a epithelioid sarcoma, a clear cell sarcoma, an extraskeletal CS, an extraskeletal OS, a malignant granular cell tumor, and 4 unclassifiable spindle cell sarcomas. Benign soft tissue tumors included 2 neurofibromatosis, 2 desmoids, a lipoma, and a chondromyxoid fibroma.the 3 metastatic cancers to the bone (a thyroid cancer, a renal cancer, and a lung cancer), and one metastatic cancer to the soft tissue (malignant melanoma) were also included. The control subjects comprised 10 males and 10 females. The mean age of the control subjects was 50 years (23-79 years). Serum sample collection Out of 77 serum samples of malignant bone and soft tissue tumors, the 57 serum samples including 22 samples from bone tumor and 35 samples from soft tissue tumors were obtained at open biopsy or initial surgical excision before administration of any chemotherapeutic agent. 20 serum samples were obtained at the excision of recurrent tumor. 22 patients of malignant bone tumors and 35 patients of malignant soft tissue tumors were primary when they were referred to our Institution and others were recurrence after initial therapy. Immunoenzymometric assay for the scd155 levels The immunoenzymometric assay for the scd155 levels was performed using the ELISA plate which can detect human CD 155, manufactured by Uscn Life Science Inc. (Wuhan,China) The procedures were performed according to the manufacturer s instructions and the final concentration was determined by optical density according to the standard curves. Statistical analysis The Mann-Whitney U test was used to analyze the associations between the serum scd155 levels and the clinicopathological variables, such as the age, gender, tumor size, histological grade, and the type of the tumors (bone or soft tissue). We defined the cut-off level of scd155 at 2.0 ng/ml to identify the high-risk patient group. The overall survival (OS) was defined as the time from the initial treatment to the date of mortality attributed to the neoplasm. The local recurrence free survival (LRFS) was defined as the time from the initial treatment to the date of clinically documented local recurrence. The metastasis free survival (MFS)was defined as the time from the initial treatment to the date of clinically documented distant metastasis. To investigate the prognostic value of the scd155 levels, Kaplan-Meier survival analyses and log-rank test were performed in the patients with primary malignant bone and soft tissue tumor. A p value < 0.05 was considered to be significant. The analysis was performed using IBM SPSS Statistics (version 20). Results: Serum scd155 levels in bone and soft tissue tumor patients and control subjects The mean serum scd155 level was 1.33 ng/ml (range, ng/ml) in all patients with tumors. The mean serum scd155 level was 1.26 ng/ml (range, ng/ml) in bone tumor patients, otherwise 1.31 ng/ml (range, 0-,13.9 ng/ml) in soft tissue tumor patients. The mean serum scd155 level was 3.03 ng/ml in patients with musculoskeletal metastases. On the other hand, The serum scd155 level was below the detection limit value(0.312ng/ml) in all control samples.(figure1,2) Associations between the serum scd155 level and the clinicopathological variables The Mann-Whitney U test was used to analyze the associations between the serum scd155 levels and the clinicopathological variables. In this study, the level of scd155 was not significantly associated with the age, gender, tumor size, origin,and the type of the tumor. (Table2) Prognostic analysis The LRFS,MFS and OS of the patients showing high scd155 group(scd ng/ml)were compared with those of patients showing low scd155 group(scd155<2.0ng/ml).kaplan-meier survival analyses and log-rank tests were performed for each primary malignant bone and soft tissue tumor

2 patients. In the 35 patients with primary malignant soft tissue tumors, patients with high scd155 levels had a poorer OS and MFS than the patients with low scd155 levels (p =0.002, P=0.030 ). (Figure3,4,5) On the other hand, the level of scd155 was not significantly associated with OS,LRFS,MFS in the 22 patients with primary malignant bone tumors. Discussion: Increased expression of CD155 have been reported in various types of cancer, including colorectal carcinoma and lung adenocarcinoma. Nakai et al. reported that the overexpression of CD155 detected by immunohistochemistry has clinical significance for the prognostic evaluation of patients with primary pulmonary adenocarcinoma.(4) Atsumi et al. reported that CD155 mrna overexpression in soft tissue sarcoma tissue samples is associated with the clinical outcome of the patients.however,there are few reports about the clinical significance of scd155 levels in cancer patients.(5)our results indicate that scd155 is present in significantly higher amounts in patients with malignant bone and soft tissue tumors than in healthy subjects. In addition, a high serum scd155 level is associated with a poor outcome in soft tissue sarcoma patients. scd155 is therefore a potentially valuable pretherapeutic factor for predicting the long-term survival in soft tissue sarcoma patients. Further studies involving a larger sample and longer follow-up are necessary to verify these results. Significance: The results of the present study suggest that scd155 was significantly associated with the prognosis of malignant soft tissue tumor and might be a biomarker for malignant soft tissue tumors. Acknowledgments: References: 1)Takai Y, et al. Cancer Sci )Kevin E Sloan et al. BMC Cancer )S.Atsumi et al. ONCOLOGY LETTERS )Nakai et al. Cancer Sci )Zhang et al.tohoku j.exp.med 2012

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5 ORS 2014 Annual Meeting Poster No: 1102

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