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Papers by Kanya Honoki

Journal of cancer, 2024

There is no doubt that anyone who has participated in cancer care or research has once read the '... more There is no doubt that anyone who has participated in cancer care or research has once read the 'Hallmarks of Cancer' papers published by Hanahan and Weinberg in 2001 and 2011. They initially defined the six qualities of cancer cells as cancer hallmarks in 2001, but expanded that to 11 as a next generation in 2011. In their papers, they discussed the potential treatment strategies against cancer corresponding to each of the 11 hallmarks, and to date, proposed therapies that target genes and signaling pathways associated with each of these hallmarks have guided a trail that cancer treatments should take, some of which are now used as standard in clinical practice and some of which have yet to progress that far. Along with the recent advances in cancer research such as genomic analysis with next generation sequencing, they can be reconverged to an alternative six categories defined as selective proliferative advantages, altered stress response, deregulated cellular metabolism, immune modulation and inflammation, tumor microenvironment, tissue invasion and metastasis. In this paper, we will overview the current state of these alternative hallmarks and their corresponding treatments in the current sarcoma practice, then discuss the future direction of sarcoma treatment.

International Journal of Molecular Sciences

5-aminolevulinic acid (ALA) is used for tumor-targeting phototherapy because it is converted to p... more 5-aminolevulinic acid (ALA) is used for tumor-targeting phototherapy because it is converted to protoporphyrin IX (PPIX) upon excitation and induces phototoxicity. However, the effect of ALA on malignant cells under unexcited conditions is unclear. This information is essential when administering ALA systemically. We used sarcoma cell lines that usually arise deep in the body and are rarely exposed to light to examine the effects of ALA treatment under light (daylight lamp irradiation) and dark (dark room) conditions. ALA-treated human SW872 liposarcoma cells and human MG63 osteosarcoma cells cultured under light exhibited growth suppression and increased oxidative stress, while cells cultured in the dark showed no change. However, sphere-forming ability increased in the dark, and the expression of stem-cell-related genes was induced in dark, but not light, conditions. ALA administration increased heme oxygenase 1 (HO-1) expression in both cell types; when carbon monoxide (CO), a me...

Current Oncology, Dec 12, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Oncology Letters, 2020

Evidence is limited regarding the immunologic profile and immune microenvironment of soft tissue ... more Evidence is limited regarding the immunologic profile and immune microenvironment of soft tissue sarcoma subtypes. The aim of the present study was to describe the clinical significance and prognostic implications of PD-L1, PD-L2, and PD-1 in patients with retroperitoneal sarcoma (RSar). In this retrospective, multicenter, collaborative study, medical charts were reviewed and the immunohistochemical staining results of resected tissue specimens from 51 patients with RSar were examined. Immunohistochemical staining was performed with primary antibodies against PD-L1, PD-L2, PD-1, and Ki-67. The correlations between the baseline clinical parameters and expression levels of the four molecules in sarcoma cells were evaluated, and their prognostic values after tumor resection were assessed. Dedifferentiated liposarcoma (41%), leiomyosarcoma (20%), and undifferentiated pleomorphic sarcoma (16%) were the three major types identified. Dedifferentiated liposarcoma and leiomyosarcoma showed higher levels of PD-L1 expression than did other sarcomas. The Spearman correlation analysis revealed that baseline serum lactate dehydrogenase levels were moderately and positively correlated with PD-L1 (P=0.02, r=0.41) and PD-L2 (P= 0.006, r= 0.47) expression. The median recurrence-free and disease-specific survival was 58 and 16 months, respectively, during the 29-month median follow-up after surgery. On univariate analysis, a higher expression level of PD-1 was associated with a higher risk of recurrence, whereas multivariate analyses revealed that independent predictors of recurrence-free and disease-specific survival indicated a high expression of Ki-67 (P= 0.03; hazard ratio, 2.29 vs. low expression) and prognostic stage IIIB (P=0.04; hazard ratio, 5.11 vs. stage I-II), respectively. Findings of the current study provide novel insights about the prognostic value of PD-L1, PD-L2, and PD-1 expression in RSar. Serum lactate dehydrogenase levels constitute a potential predictor of PD-L1 and PD-L2 expression levels in RSar. Further investigations are needed to determine the immunologic landscape of RSar and provide a foundation for therapeutic intervention using immune checkpoint inhibitors.

Background Cervical spine metastasis worsens the quality of life (QOL) of patients with cancer. W... more Background Cervical spine metastasis worsens the quality of life (QOL) of patients with cancer. While the beneficial effects of surgery have been reported, the detailed course of functional recovery remains unclear, especially in the acute phase of rehabilitation. We previously reported on impairment-driven rehabilitation in patients with thoracic or lumbar level metastases. The present study assessed the effects of an impairment-driven strategy on the early recovery of ambulatory function in patients with cervical spine metastasis. Methods We retrospectively reviewed 13 consecutive patients with cervical neoplastic spinal compression. The patients were those whose primary impairment with spinal instability identified by a multidisciplinary tumor board who underwent palliative spine surgery. In addition, we examined neurological deficits; ambulation status; pathological fracture, collapse, and postoperative implant failure progress; and Barthel Index (BI). Results The average durati...

Toxicologic Pathology, 2000

We recently obtained 3 cloned cell lines demonstrating the p53 mutation from a lung metastatic no... more We recently obtained 3 cloned cell lines demonstrating the p53 mutation from a lung metastatic nodule of a rat transplantable osteosarcoma. In this study, we applied wild-type p53 gene transfer to the rat osteosarcoma cells by lipofection to investigate the effects on cell growth, expression of genes such as waf1/p21, bcl-2, and bax, and nucleosomal DNA fragmentation due to apoptosis. Reconstitution of the p53 gene inhibits cellular growth, and this growth-suppressive effect is partly due to apoptosis involving bcl-2 gene suppression in this tumor type. This rat osteosarcoma model is similar in biologic behavior to human cases and thus is very suitable for further investigation of tumorigenesis and gene therapy for osteosarcoma.

Experimental cell research, Jan 30, 2018

Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors mediates various biolog... more Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors mediates various biological effects in cancer cells. This study aimed to investigate the roles of LPA receptors in the regulation of cellular functions during tumor progression in osteosarcoma cells. Long-term cisplatin (CDDP)-treated MG63-C and MG63-R7-C cells were generated from osteosarcoma MG-63 and highly-migratory MG63-R7 cells, respectively. LPAR2 and LPAR3 expression levels were significantly higher in MG63-C cells than in MG-63 cells, while LPAR1 expression was reduced. MG63-C cells were highly motile, compared with MG-63 cells. MG63-C cell motility was suppressed by LPA knockdown and enhanced by the LPA/LPA antagonist, dioctanoylglycerol pyrophosphate. LPAR2 and LPAR3 expression levels were significantly elevated in MG63-R7-C cells in comparison with MG63-R7 cells. MG63-R7-C cells were found to be highly invasive, correlating with metalloproteinase-2 activation. MG63-R7-C cells formed large colonies,...

Progress in Rehabilitation Medicine, 2016

Radiotherapy is an essential component of curative or palliative therapy for patients with uterin... more Radiotherapy is an essential component of curative or palliative therapy for patients with uterine cervical cancer. Although advances in radiotherapy have led to longer survival, survivors may consequently be at risk of pelvic insufficiency fracture (PIF). We retrospectively reviewed medical records and clinical outcomes to assess the impact of PIF on walking disability. Methods: Between January 2002 and December 2009, 145 uterine cancer patients treated with radiotherapy in our hospital were reviewed. Among these, 15 patients (10.3%) were diagnosed with PIF. The types of fractures were identified according to the AO/OTA classification system. Medical records were examined to establish the time to first diagnosis of PIF, the type of fracture, and clinical outcomes. Disability was assessed using Barthel index mobility scores. Results: The median time to PIF detection was 16 months. Of the 15 patients with PIF, 14 had type B fractures (7 cases of B2 and 7 cases of B3) and 1 had a type C fracture. Among 11 patients with pelvic pain, 6 achieved pain control but 5 patients with bilateral lesions in the posterior arch or lateral compression of the sacrum developed pain that finally resulted in walking disability and a lower performance status. Conclusions: PIF causes severe motor disturbance in patients with unstable fracture types. Routine imaging checkups were useful during the 5 years after completion of radiotherapy; in nine patients the fracture progressed for longer than 1 year. In cancer rehabilitation for PIF patients, continuous assessment is essential for predicting walking disability.

European journal of orthopaedic surgery & traumatology : orthopedie traumatologie, 2017

The treatment of giant cell tumor (GCT) of bone remains controversial. Intralesional surgery (cur... more The treatment of giant cell tumor (GCT) of bone remains controversial. Intralesional surgery (curettage) results in a higher rate of local recurrence, but better functional results compared to resection. The aim of this study was to assess whether the use of curettage was successful in the treatment of GCT of long bones. We evaluated the influence of adjuvant treatment, local tumor presentation, and demographic factors on the risk of recurrence. We retrospectively reviewed the records of patients treated for GCT of long bones between 1990 and 2013, using curettage. No patient had any treatment other than surgery. After detailed curettage, the bone cavity was filled with bone allografts and/or cement. Recurrence rates, risk factors for recurrence and the development of pulmonary metastases were determined. The minimum follow-up was 24 months. We enrolled 210 patients with GCT of long bones treated by curettage. The rate of local recurrence was 16.2% (34/210 patients). The median foll...

European journal of orthopaedic surgery & traumatology : orthopedie traumatologie, Jan 13, 2017

The purpose of our study is to verify possible clinical and radiological findings with regard to ... more The purpose of our study is to verify possible clinical and radiological findings with regard to distinguishing enchondroma from atypical cartilaginous tumour (ACT). In addition, this study determined risk factors that are associated with local recurrence of enchondroma or ACT treated with curettage. We retrospectively reviewed the records of 54 patients with enchondroma and 35 patients with ACT of the long bones treated by curettage between 1986 and 2015. The minimum follow-up was 18 months. The relationship between clinical and radiological factors and the tumour type or local recurrence was assessed using Chi-square test or Fischer exact test. Endosteal scalloping (p = 0.004) and soft tissue extension (p = 0.017) were shown to statistically favour ACT over enchondroma; by contrast, pain (p = 0.034) was more frequent in enchondroma compared to ACT. All patients with enchondroma had no local recurrence; in contrast, local recurrence occurred in four patients with ACT (11%). Soft ti...

World Journal of Stem Cells, 2017

Characterized by dysfunction of tissues, organs, organ systems and the whole organism, aging resu... more Characterized by dysfunction of tissues, organs, organ systems and the whole organism, aging results from

Cancer Research, 2013

Lysophosphatidic acid (LPA) acts through G-protein coupled transmembrane receptors, and at least ... more Lysophosphatidic acid (LPA) acts through G-protein coupled transmembrane receptors, and at least 6 types of LPA receptors (LPARs) have been identified. They regulate many different cellular responses, such as proliferation, survival, differentiation, migration, cytoskeletal changes and calcium influx through these pathways, and may act as a positive or negative regulator of cancer cell behaviors in a receptor specific manner which depends on cell types. Gene expression profiles analyzed in rat sarcoma model showed highly metastatic osteosarcoma cells expressing abundant LPA receptor-3 (LPAR3) compared to mesenchymal stem cells and non-metastatic MFH cells. In the current study, we generated LPAR3-knockdown cells from human fibrosarcoma HT1080 and osteosarcoma HOS cells by transfection with shRNA plasmids and investigated the involvement of LPA3 pathway for cell migration and invasion abilities. Both sarcoma cells expressed through LPAR1 to 5 except for LPAR1 in osteosarcoma HOS. Fir...

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association, 2011

Abdominosacral amputation is a potentially curative surgical approach for patients with recurrent... more Abdominosacral amputation is a potentially curative surgical approach for patients with recurrent rectal cancer. Previous reports have described differing extents of sacral resection. Most of these reports stated that high sacral involvement of the tumor is a contraindication for surgery; however, the basis for this is unclear. In this study, we reviewed the highest level of sacral amputation and the "contraindications" for this technique. Using a systematic literature survey, we analyzed the theoretical basis and the changes in surgical indications for recurrent rectal cancer. We retrieved 33 articles from Medline and one study from the Cochrane Center Register of Controlled Trials. The highest level of resection was at the level of L5/S and S1 in one article, S1/2 and S2 in nine articles and S2/3 and S3 in 11 articles. Fifteen articles stated contraindications regarding sacral level, including tumor involvement of S1, the S1/2 junction, or the level above the S2/3 juncti...

Molecular and Cellular Biochemistry, 2014

G-protein-coupled receptor 120 (GPR120) is identified as a G-protein-coupled receptor for unsatur... more G-protein-coupled receptor 120 (GPR120) is identified as a G-protein-coupled receptor for unsaturated long-chain free fatty acids that mediates insulin signaling and anti-inflammatory effects. Recently, it has been reported that GPR120 promotes the cell motile activity and angiogenesis in cancer cells. In this study, we assessed the role of GPR120 in the cell motile activity induced by 12-Otetradecanoylphorbol-13-acetate (TPA) in rat liver epithelial WB-F344 cells. Cells were treated with TPA at a concentration of 5 nM for 72 h. The expression level of the Gpr120 gene was measured by quantitative real-time RT-PCR analysis. Cells treated with TPA showed the elevated Gpr120 expression, in comparison with untreated cells. In cell motility assays, the cell motile activity of cells treated with TPA was significantly higher than that of untreated cells. To confirm whether GPR120 is involved in the cell motile activity mediated by TPA, we generated GPR120 knockdown cells from WB-F344 cells. The cell motile activity induced by TPA was significantly suppressed by GPR120 knockdown. These results suggest that GPR120 plays an important role in the cell motile activity induced by TPA in WB-F344 cells.

Molecular Carcinogenesis, 2011

Aberrant expressions of lysophosphatidic acid (LPA) receptor genes have been reported in tumor ce... more Aberrant expressions of lysophosphatidic acid (LPA) receptor genes have been reported in tumor cells. Here, we measured the expression levels of the Lpa5 gene and its DNA methylation status in rat tumor cells, and investigated cell growth effects of LPA in Lpa5 expressed cells. Real-time reverse transcription (RT)-polymerase chain reaction (PCR) analysis revealed that increased expressions of the Lpa5 gene were detected in rat liver-derived hepatoma RH7777 and lung-derived adenocarcinoma RLCNR cells. For the analysis of methylation status, bisulfite sequencing was performed with RH7777 and RLCNR cells and compared with other tumor cells and liver epithelial cells. The Lpa5 gene in Lpa5 unexpressed cells and liver epithelial cells were highly methylated in the 5' upstream region. In contrast, the Lpa5 gene in RH7777 and RLCNR cells was unmethylated, correlating with increased expressions of Lpa5. In the assays for cell growth effects of LPA, LPA enhanced cell proliferation and motility in RH7777 and RLCNR cells. LPA also stimulated cell invasion in RLCNR, but not in RH7777 cells. In rat liver and lung tumors induced by nitroso-compounds, 4 out of 6 hepatocellular carcinomas and 5 out of 6 lung adenocarcinomas indicated increased expressions of Lpa5 with unmethylated status. These results suggest that increased Lpa5 expressions due to aberrant DNA methylation may be involved in the acquisition of growth advantage of rat tumor cells.

Molecular Carcinogenesis, 1992

The expression of the transin, c‐fos, and c‐jun genes was assessed in transplantable osteosarcoma... more The expression of the transin, c‐fos, and c‐jun genes was assessed in transplantable osteosarcomas and malignant fibrous histiocytomas, as well as in pancreatic duct adenocarcinomas and hepatocellular carcinomas of rats and hamsters. Northern blot analysis revealed that both an undifferentiated osteosarcoma of spontaneous origin (SOS) and 4‐hydroxyaminoquinoline 1‐oxide (4‐HAQO)‐induced malignant fibrous histiocytomas with metastatic potential to the lung showed remarkably increased expression of transin mRNA transcripts. This was not the case for the other tumors. Interestingly, levels of transin mRNA were lower in lung metastatic lesions than in primary subcutaneous SOS tumors. The primary SOS and MFH expressed both c‐fos and c‐jun genes in conjunction with the transin gene, whereas the non‐transin expressers, a 4‐HAQO‐induced osteosarcoma (COS) and the pancreatic duct adenocarcinomas, demonstrated one or the other, but not both. These results suggest a possible involvement of tra...

Molecular Carcinogenesis, 2006

The study aimed to assess the involvement of aberrant DNA methylation in lung carcinogenesis by m... more The study aimed to assess the involvement of aberrant DNA methylation in lung carcinogenesis by measuring expressions of E-cadherin and p16 genes, and their DNA methylation status in the 5' upstream region in rat lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine (BHP). Six-week-old male Wistar rats were given 2000 ppm BHP in their drinking water for 12 wk, and maintained without further treatment until they were sacrificed at 25 wk. A total of nine lung adenocarcinomas were collected, and total RNA from each sample was extracted for assessment of gene expression by real-time reverse transcription (RT)-polymerase chain reaction (PCR). Expressions of E-cadherin and p16 genes were significantly reduced in lung adenocarcinomas (P < 0.05 and P < 0.005, respectively) compared with normal lung tissues. For methylation analysis, bisulfite sequencing was performed using two normal lung tissues and five tumors. The two normal lung tissues were all unmethylated in regions of E-cadherin and p16. In contrast, five adenocarcinomas were highly methylated, and these aberrant methylation patterns correlated with reduced expressions of E-cadherin and p16. These results suggest that aberrant DNA methylation of E-cadherin and p16 genes may play important roles in development of lung adenocarcinomas induced by BHP in rats.

Molecular Carcinogenesis, 2007

DAL‐1 (differentially expressed in adenocarcinoma of the lung) is an actin‐binding protein that h... more DAL‐1 (differentially expressed in adenocarcinoma of the lung) is an actin‐binding protein that has been shown to suppress growth in lung cancer cells. Recently, inactivation of the gene encoding DAL‐1 due to hypermethylation has been found in several human malignancies, including lung cancers. To assess the involvement of the Dal‐1 gene in rat lung carcinogenesis, we investigated the expression of Dal1 and its methylation status in rat lung adenocarcinomas induced by N‐nitrosobis(2‐hydroxypropyl)amine (BHP). Six‐week old male Wistar rats (n = 11) were given 2000 ppm BHP in their drinking water for 12 wk and maintained without further treatment until they were sacrificed at 25 wk. Total RNA was extracted from 11 lung adenocarcinomas, one from each BHP treated rat, and Dal‐1 gene expression was analyzed using real‐time quantitative reverse transcription‐polymerase chain reaction. Dal‐1 expression was significantly reduced in the lung adenocarcinomas compared with three normal lung ti...

Molecular Carcinogenesis, 2011

Lysophosphatidic acid (LPA), which interacts with G protein-coupled transmembrane LPA receptors e... more Lysophosphatidic acid (LPA), which interacts with G protein-coupled transmembrane LPA receptors exhibits several biological effects, such as cell proliferation, migration, and differentiation. Recently, it has been reported that alteration of LPA receptor genes occurs in several cancer cells. In this study, to assess the biological role of LPA receptor-3 (LPA 3) in the pathogenesis of tumor cells, we generated the Lpar3-expressing cells (RHa3B12 and RHa3G8) from rat hepatoma RH7777 cells, and examined their abilities of cell migration and tumorigenicity, compared with the Lpar3unexpressing cells. In cell motility and invasion assays, RHa3B12 and RHa3G8 cells showed significantly higher intrinsic activity without LPA treatment than control RH7777AB cells. LPA treatment further increased cell motility and invasion of these cells. The cell motility of RHa3B12 and RHa3G8 cells stimulated by LPA treatment was significantly suppressed by pretreatment with inhibitors of Gi or Gq proteins. In a soft agar assay, the large sized colonies were formed in RHa3B12 and RHa3G8 cells, but not in RH7777AB cells. The cell survival of RHa3G8 cells treated with cisplatin (CDDP) or doxorubicin (DOX) was higher than that of RH7777AB cells, correlating with the elevated expression levels of multidrug-resistance related genes, Mdr1a, Mdr1b, and Gstp1. These results suggest that LPA 3 may be involved in progression and aggressiveness of rat hepatoma RH7777 cells.

Journal of cancer, 2024

There is no doubt that anyone who has participated in cancer care or research has once read the '... more There is no doubt that anyone who has participated in cancer care or research has once read the 'Hallmarks of Cancer' papers published by Hanahan and Weinberg in 2001 and 2011. They initially defined the six qualities of cancer cells as cancer hallmarks in 2001, but expanded that to 11 as a next generation in 2011. In their papers, they discussed the potential treatment strategies against cancer corresponding to each of the 11 hallmarks, and to date, proposed therapies that target genes and signaling pathways associated with each of these hallmarks have guided a trail that cancer treatments should take, some of which are now used as standard in clinical practice and some of which have yet to progress that far. Along with the recent advances in cancer research such as genomic analysis with next generation sequencing, they can be reconverged to an alternative six categories defined as selective proliferative advantages, altered stress response, deregulated cellular metabolism, immune modulation and inflammation, tumor microenvironment, tissue invasion and metastasis. In this paper, we will overview the current state of these alternative hallmarks and their corresponding treatments in the current sarcoma practice, then discuss the future direction of sarcoma treatment.

International Journal of Molecular Sciences

5-aminolevulinic acid (ALA) is used for tumor-targeting phototherapy because it is converted to p... more 5-aminolevulinic acid (ALA) is used for tumor-targeting phototherapy because it is converted to protoporphyrin IX (PPIX) upon excitation and induces phototoxicity. However, the effect of ALA on malignant cells under unexcited conditions is unclear. This information is essential when administering ALA systemically. We used sarcoma cell lines that usually arise deep in the body and are rarely exposed to light to examine the effects of ALA treatment under light (daylight lamp irradiation) and dark (dark room) conditions. ALA-treated human SW872 liposarcoma cells and human MG63 osteosarcoma cells cultured under light exhibited growth suppression and increased oxidative stress, while cells cultured in the dark showed no change. However, sphere-forming ability increased in the dark, and the expression of stem-cell-related genes was induced in dark, but not light, conditions. ALA administration increased heme oxygenase 1 (HO-1) expression in both cell types; when carbon monoxide (CO), a me...

Current Oncology, Dec 12, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Oncology Letters, 2020

Evidence is limited regarding the immunologic profile and immune microenvironment of soft tissue ... more Evidence is limited regarding the immunologic profile and immune microenvironment of soft tissue sarcoma subtypes. The aim of the present study was to describe the clinical significance and prognostic implications of PD-L1, PD-L2, and PD-1 in patients with retroperitoneal sarcoma (RSar). In this retrospective, multicenter, collaborative study, medical charts were reviewed and the immunohistochemical staining results of resected tissue specimens from 51 patients with RSar were examined. Immunohistochemical staining was performed with primary antibodies against PD-L1, PD-L2, PD-1, and Ki-67. The correlations between the baseline clinical parameters and expression levels of the four molecules in sarcoma cells were evaluated, and their prognostic values after tumor resection were assessed. Dedifferentiated liposarcoma (41%), leiomyosarcoma (20%), and undifferentiated pleomorphic sarcoma (16%) were the three major types identified. Dedifferentiated liposarcoma and leiomyosarcoma showed higher levels of PD-L1 expression than did other sarcomas. The Spearman correlation analysis revealed that baseline serum lactate dehydrogenase levels were moderately and positively correlated with PD-L1 (P=0.02, r=0.41) and PD-L2 (P= 0.006, r= 0.47) expression. The median recurrence-free and disease-specific survival was 58 and 16 months, respectively, during the 29-month median follow-up after surgery. On univariate analysis, a higher expression level of PD-1 was associated with a higher risk of recurrence, whereas multivariate analyses revealed that independent predictors of recurrence-free and disease-specific survival indicated a high expression of Ki-67 (P= 0.03; hazard ratio, 2.29 vs. low expression) and prognostic stage IIIB (P=0.04; hazard ratio, 5.11 vs. stage I-II), respectively. Findings of the current study provide novel insights about the prognostic value of PD-L1, PD-L2, and PD-1 expression in RSar. Serum lactate dehydrogenase levels constitute a potential predictor of PD-L1 and PD-L2 expression levels in RSar. Further investigations are needed to determine the immunologic landscape of RSar and provide a foundation for therapeutic intervention using immune checkpoint inhibitors.

Background Cervical spine metastasis worsens the quality of life (QOL) of patients with cancer. W... more Background Cervical spine metastasis worsens the quality of life (QOL) of patients with cancer. While the beneficial effects of surgery have been reported, the detailed course of functional recovery remains unclear, especially in the acute phase of rehabilitation. We previously reported on impairment-driven rehabilitation in patients with thoracic or lumbar level metastases. The present study assessed the effects of an impairment-driven strategy on the early recovery of ambulatory function in patients with cervical spine metastasis. Methods We retrospectively reviewed 13 consecutive patients with cervical neoplastic spinal compression. The patients were those whose primary impairment with spinal instability identified by a multidisciplinary tumor board who underwent palliative spine surgery. In addition, we examined neurological deficits; ambulation status; pathological fracture, collapse, and postoperative implant failure progress; and Barthel Index (BI). Results The average durati...

Toxicologic Pathology, 2000

We recently obtained 3 cloned cell lines demonstrating the p53 mutation from a lung metastatic no... more We recently obtained 3 cloned cell lines demonstrating the p53 mutation from a lung metastatic nodule of a rat transplantable osteosarcoma. In this study, we applied wild-type p53 gene transfer to the rat osteosarcoma cells by lipofection to investigate the effects on cell growth, expression of genes such as waf1/p21, bcl-2, and bax, and nucleosomal DNA fragmentation due to apoptosis. Reconstitution of the p53 gene inhibits cellular growth, and this growth-suppressive effect is partly due to apoptosis involving bcl-2 gene suppression in this tumor type. This rat osteosarcoma model is similar in biologic behavior to human cases and thus is very suitable for further investigation of tumorigenesis and gene therapy for osteosarcoma.

Experimental cell research, Jan 30, 2018

Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors mediates various biolog... more Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors mediates various biological effects in cancer cells. This study aimed to investigate the roles of LPA receptors in the regulation of cellular functions during tumor progression in osteosarcoma cells. Long-term cisplatin (CDDP)-treated MG63-C and MG63-R7-C cells were generated from osteosarcoma MG-63 and highly-migratory MG63-R7 cells, respectively. LPAR2 and LPAR3 expression levels were significantly higher in MG63-C cells than in MG-63 cells, while LPAR1 expression was reduced. MG63-C cells were highly motile, compared with MG-63 cells. MG63-C cell motility was suppressed by LPA knockdown and enhanced by the LPA/LPA antagonist, dioctanoylglycerol pyrophosphate. LPAR2 and LPAR3 expression levels were significantly elevated in MG63-R7-C cells in comparison with MG63-R7 cells. MG63-R7-C cells were found to be highly invasive, correlating with metalloproteinase-2 activation. MG63-R7-C cells formed large colonies,...

Progress in Rehabilitation Medicine, 2016

Radiotherapy is an essential component of curative or palliative therapy for patients with uterin... more Radiotherapy is an essential component of curative or palliative therapy for patients with uterine cervical cancer. Although advances in radiotherapy have led to longer survival, survivors may consequently be at risk of pelvic insufficiency fracture (PIF). We retrospectively reviewed medical records and clinical outcomes to assess the impact of PIF on walking disability. Methods: Between January 2002 and December 2009, 145 uterine cancer patients treated with radiotherapy in our hospital were reviewed. Among these, 15 patients (10.3%) were diagnosed with PIF. The types of fractures were identified according to the AO/OTA classification system. Medical records were examined to establish the time to first diagnosis of PIF, the type of fracture, and clinical outcomes. Disability was assessed using Barthel index mobility scores. Results: The median time to PIF detection was 16 months. Of the 15 patients with PIF, 14 had type B fractures (7 cases of B2 and 7 cases of B3) and 1 had a type C fracture. Among 11 patients with pelvic pain, 6 achieved pain control but 5 patients with bilateral lesions in the posterior arch or lateral compression of the sacrum developed pain that finally resulted in walking disability and a lower performance status. Conclusions: PIF causes severe motor disturbance in patients with unstable fracture types. Routine imaging checkups were useful during the 5 years after completion of radiotherapy; in nine patients the fracture progressed for longer than 1 year. In cancer rehabilitation for PIF patients, continuous assessment is essential for predicting walking disability.

European journal of orthopaedic surgery & traumatology : orthopedie traumatologie, 2017

The treatment of giant cell tumor (GCT) of bone remains controversial. Intralesional surgery (cur... more The treatment of giant cell tumor (GCT) of bone remains controversial. Intralesional surgery (curettage) results in a higher rate of local recurrence, but better functional results compared to resection. The aim of this study was to assess whether the use of curettage was successful in the treatment of GCT of long bones. We evaluated the influence of adjuvant treatment, local tumor presentation, and demographic factors on the risk of recurrence. We retrospectively reviewed the records of patients treated for GCT of long bones between 1990 and 2013, using curettage. No patient had any treatment other than surgery. After detailed curettage, the bone cavity was filled with bone allografts and/or cement. Recurrence rates, risk factors for recurrence and the development of pulmonary metastases were determined. The minimum follow-up was 24 months. We enrolled 210 patients with GCT of long bones treated by curettage. The rate of local recurrence was 16.2% (34/210 patients). The median foll...

European journal of orthopaedic surgery & traumatology : orthopedie traumatologie, Jan 13, 2017

The purpose of our study is to verify possible clinical and radiological findings with regard to ... more The purpose of our study is to verify possible clinical and radiological findings with regard to distinguishing enchondroma from atypical cartilaginous tumour (ACT). In addition, this study determined risk factors that are associated with local recurrence of enchondroma or ACT treated with curettage. We retrospectively reviewed the records of 54 patients with enchondroma and 35 patients with ACT of the long bones treated by curettage between 1986 and 2015. The minimum follow-up was 18 months. The relationship between clinical and radiological factors and the tumour type or local recurrence was assessed using Chi-square test or Fischer exact test. Endosteal scalloping (p = 0.004) and soft tissue extension (p = 0.017) were shown to statistically favour ACT over enchondroma; by contrast, pain (p = 0.034) was more frequent in enchondroma compared to ACT. All patients with enchondroma had no local recurrence; in contrast, local recurrence occurred in four patients with ACT (11%). Soft ti...

World Journal of Stem Cells, 2017

Characterized by dysfunction of tissues, organs, organ systems and the whole organism, aging resu... more Characterized by dysfunction of tissues, organs, organ systems and the whole organism, aging results from

Cancer Research, 2013

Lysophosphatidic acid (LPA) acts through G-protein coupled transmembrane receptors, and at least ... more Lysophosphatidic acid (LPA) acts through G-protein coupled transmembrane receptors, and at least 6 types of LPA receptors (LPARs) have been identified. They regulate many different cellular responses, such as proliferation, survival, differentiation, migration, cytoskeletal changes and calcium influx through these pathways, and may act as a positive or negative regulator of cancer cell behaviors in a receptor specific manner which depends on cell types. Gene expression profiles analyzed in rat sarcoma model showed highly metastatic osteosarcoma cells expressing abundant LPA receptor-3 (LPAR3) compared to mesenchymal stem cells and non-metastatic MFH cells. In the current study, we generated LPAR3-knockdown cells from human fibrosarcoma HT1080 and osteosarcoma HOS cells by transfection with shRNA plasmids and investigated the involvement of LPA3 pathway for cell migration and invasion abilities. Both sarcoma cells expressed through LPAR1 to 5 except for LPAR1 in osteosarcoma HOS. Fir...

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association, 2011

Abdominosacral amputation is a potentially curative surgical approach for patients with recurrent... more Abdominosacral amputation is a potentially curative surgical approach for patients with recurrent rectal cancer. Previous reports have described differing extents of sacral resection. Most of these reports stated that high sacral involvement of the tumor is a contraindication for surgery; however, the basis for this is unclear. In this study, we reviewed the highest level of sacral amputation and the "contraindications" for this technique. Using a systematic literature survey, we analyzed the theoretical basis and the changes in surgical indications for recurrent rectal cancer. We retrieved 33 articles from Medline and one study from the Cochrane Center Register of Controlled Trials. The highest level of resection was at the level of L5/S and S1 in one article, S1/2 and S2 in nine articles and S2/3 and S3 in 11 articles. Fifteen articles stated contraindications regarding sacral level, including tumor involvement of S1, the S1/2 junction, or the level above the S2/3 juncti...

Molecular and Cellular Biochemistry, 2014

G-protein-coupled receptor 120 (GPR120) is identified as a G-protein-coupled receptor for unsatur... more G-protein-coupled receptor 120 (GPR120) is identified as a G-protein-coupled receptor for unsaturated long-chain free fatty acids that mediates insulin signaling and anti-inflammatory effects. Recently, it has been reported that GPR120 promotes the cell motile activity and angiogenesis in cancer cells. In this study, we assessed the role of GPR120 in the cell motile activity induced by 12-Otetradecanoylphorbol-13-acetate (TPA) in rat liver epithelial WB-F344 cells. Cells were treated with TPA at a concentration of 5 nM for 72 h. The expression level of the Gpr120 gene was measured by quantitative real-time RT-PCR analysis. Cells treated with TPA showed the elevated Gpr120 expression, in comparison with untreated cells. In cell motility assays, the cell motile activity of cells treated with TPA was significantly higher than that of untreated cells. To confirm whether GPR120 is involved in the cell motile activity mediated by TPA, we generated GPR120 knockdown cells from WB-F344 cells. The cell motile activity induced by TPA was significantly suppressed by GPR120 knockdown. These results suggest that GPR120 plays an important role in the cell motile activity induced by TPA in WB-F344 cells.

Molecular Carcinogenesis, 2011

Aberrant expressions of lysophosphatidic acid (LPA) receptor genes have been reported in tumor ce... more Aberrant expressions of lysophosphatidic acid (LPA) receptor genes have been reported in tumor cells. Here, we measured the expression levels of the Lpa5 gene and its DNA methylation status in rat tumor cells, and investigated cell growth effects of LPA in Lpa5 expressed cells. Real-time reverse transcription (RT)-polymerase chain reaction (PCR) analysis revealed that increased expressions of the Lpa5 gene were detected in rat liver-derived hepatoma RH7777 and lung-derived adenocarcinoma RLCNR cells. For the analysis of methylation status, bisulfite sequencing was performed with RH7777 and RLCNR cells and compared with other tumor cells and liver epithelial cells. The Lpa5 gene in Lpa5 unexpressed cells and liver epithelial cells were highly methylated in the 5' upstream region. In contrast, the Lpa5 gene in RH7777 and RLCNR cells was unmethylated, correlating with increased expressions of Lpa5. In the assays for cell growth effects of LPA, LPA enhanced cell proliferation and motility in RH7777 and RLCNR cells. LPA also stimulated cell invasion in RLCNR, but not in RH7777 cells. In rat liver and lung tumors induced by nitroso-compounds, 4 out of 6 hepatocellular carcinomas and 5 out of 6 lung adenocarcinomas indicated increased expressions of Lpa5 with unmethylated status. These results suggest that increased Lpa5 expressions due to aberrant DNA methylation may be involved in the acquisition of growth advantage of rat tumor cells.

Molecular Carcinogenesis, 1992

The expression of the transin, c‐fos, and c‐jun genes was assessed in transplantable osteosarcoma... more The expression of the transin, c‐fos, and c‐jun genes was assessed in transplantable osteosarcomas and malignant fibrous histiocytomas, as well as in pancreatic duct adenocarcinomas and hepatocellular carcinomas of rats and hamsters. Northern blot analysis revealed that both an undifferentiated osteosarcoma of spontaneous origin (SOS) and 4‐hydroxyaminoquinoline 1‐oxide (4‐HAQO)‐induced malignant fibrous histiocytomas with metastatic potential to the lung showed remarkably increased expression of transin mRNA transcripts. This was not the case for the other tumors. Interestingly, levels of transin mRNA were lower in lung metastatic lesions than in primary subcutaneous SOS tumors. The primary SOS and MFH expressed both c‐fos and c‐jun genes in conjunction with the transin gene, whereas the non‐transin expressers, a 4‐HAQO‐induced osteosarcoma (COS) and the pancreatic duct adenocarcinomas, demonstrated one or the other, but not both. These results suggest a possible involvement of tra...

Molecular Carcinogenesis, 2006

The study aimed to assess the involvement of aberrant DNA methylation in lung carcinogenesis by m... more The study aimed to assess the involvement of aberrant DNA methylation in lung carcinogenesis by measuring expressions of E-cadherin and p16 genes, and their DNA methylation status in the 5' upstream region in rat lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine (BHP). Six-week-old male Wistar rats were given 2000 ppm BHP in their drinking water for 12 wk, and maintained without further treatment until they were sacrificed at 25 wk. A total of nine lung adenocarcinomas were collected, and total RNA from each sample was extracted for assessment of gene expression by real-time reverse transcription (RT)-polymerase chain reaction (PCR). Expressions of E-cadherin and p16 genes were significantly reduced in lung adenocarcinomas (P < 0.05 and P < 0.005, respectively) compared with normal lung tissues. For methylation analysis, bisulfite sequencing was performed using two normal lung tissues and five tumors. The two normal lung tissues were all unmethylated in regions of E-cadherin and p16. In contrast, five adenocarcinomas were highly methylated, and these aberrant methylation patterns correlated with reduced expressions of E-cadherin and p16. These results suggest that aberrant DNA methylation of E-cadherin and p16 genes may play important roles in development of lung adenocarcinomas induced by BHP in rats.

Molecular Carcinogenesis, 2007

DAL‐1 (differentially expressed in adenocarcinoma of the lung) is an actin‐binding protein that h... more DAL‐1 (differentially expressed in adenocarcinoma of the lung) is an actin‐binding protein that has been shown to suppress growth in lung cancer cells. Recently, inactivation of the gene encoding DAL‐1 due to hypermethylation has been found in several human malignancies, including lung cancers. To assess the involvement of the Dal‐1 gene in rat lung carcinogenesis, we investigated the expression of Dal1 and its methylation status in rat lung adenocarcinomas induced by N‐nitrosobis(2‐hydroxypropyl)amine (BHP). Six‐week old male Wistar rats (n = 11) were given 2000 ppm BHP in their drinking water for 12 wk and maintained without further treatment until they were sacrificed at 25 wk. Total RNA was extracted from 11 lung adenocarcinomas, one from each BHP treated rat, and Dal‐1 gene expression was analyzed using real‐time quantitative reverse transcription‐polymerase chain reaction. Dal‐1 expression was significantly reduced in the lung adenocarcinomas compared with three normal lung ti...

Molecular Carcinogenesis, 2011

Lysophosphatidic acid (LPA), which interacts with G protein-coupled transmembrane LPA receptors e... more Lysophosphatidic acid (LPA), which interacts with G protein-coupled transmembrane LPA receptors exhibits several biological effects, such as cell proliferation, migration, and differentiation. Recently, it has been reported that alteration of LPA receptor genes occurs in several cancer cells. In this study, to assess the biological role of LPA receptor-3 (LPA 3) in the pathogenesis of tumor cells, we generated the Lpar3-expressing cells (RHa3B12 and RHa3G8) from rat hepatoma RH7777 cells, and examined their abilities of cell migration and tumorigenicity, compared with the Lpar3unexpressing cells. In cell motility and invasion assays, RHa3B12 and RHa3G8 cells showed significantly higher intrinsic activity without LPA treatment than control RH7777AB cells. LPA treatment further increased cell motility and invasion of these cells. The cell motility of RHa3B12 and RHa3G8 cells stimulated by LPA treatment was significantly suppressed by pretreatment with inhibitors of Gi or Gq proteins. In a soft agar assay, the large sized colonies were formed in RHa3B12 and RHa3G8 cells, but not in RH7777AB cells. The cell survival of RHa3G8 cells treated with cisplatin (CDDP) or doxorubicin (DOX) was higher than that of RH7777AB cells, correlating with the elevated expression levels of multidrug-resistance related genes, Mdr1a, Mdr1b, and Gstp1. These results suggest that LPA 3 may be involved in progression and aggressiveness of rat hepatoma RH7777 cells.