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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.

in Vivo, 2008

2-Methoxyestradiol (2-ME) has been found to possess antitumor activity in vivo and in vitro. It h... more 2-Methoxyestradiol (2-ME) has been found to possess antitumor activity in vivo and in vitro. It has been suggested that 2-ME induces apoptosis resulting in G 2 /M arrest of tumor cells. In this study, the effect of 2-ME was evaluated in rat osteosarcoma and malignant fibrous histiocytoma (MFH) cell lines. 2-ME was used at final concentrations of 100 nM to 2 ÌM. The effect of 2-ME on cell growth was measured by the MTS assay. Induction of apoptosis and activation of caspase-3 were investigated along with apoptosis-related gene expression. The data showed that 2-ME significantly inhibited cell growth, inducing apoptosis. The activity of caspase-3 was increased at 20 h and 40 h in both cell lines. 2-ME induced p16 expression, which was possibly involved in the apoptotic process. These results suggested that the 2-ME-induced apoptosis of rat osteosarcoma and rat MFH cells was accompanied by caspase-3 activation through p16 induction.

Oncology Letters, Dec 6, 2021

Endosialin/CD248/tumor endothelial marker 1 is classified as a C-type lectin-like transmembrane r... more Endosialin/CD248/tumor endothelial marker 1 is classified as a C-type lectin-like transmembrane receptor, found on the plasma membrane of activated mesenchymal cells, which binds to fibronectin. Although endosialin is expressed at high levels in stem-like cells of sarcomas, its role has not been fully uncovered. The present study aimed to determine whether endosialin expression is associated with tumor progression and metastasis, and whether endosialin has the potential to act as a novel therapeutic target in osteosarcoma (OS) using MORAb-004/ontuxizumab, a humanized monoclonal antibody, which targets the type C lectin domain of endosialin. The results demonstrated that endosialin was highly expressed in OSs with metastatic disease. Furthermore, MORAb-004 had no cytostatic effect on OS cells in vitro and did not change the expression of stem cells and differentiation markers; however, it inhibited migration of OS cells. Taken together, these results suggest that endosialin may play a role in migration, and may be involved in the metastatic process of OSs. Furthermore, MORAb-004 reduces the motility of OS cells, and suppresses invasion and the development of metastatic lesions.

PubMed, May 1, 1996

Rearrangement of the MLL (myeloid-lymphoid or mixed-lineage leukemia) gene through a reciprocal c... more Rearrangement of the MLL (myeloid-lymphoid or mixed-lineage leukemia) gene through a reciprocal chromosomal translocation is found in 5% of adult acute myeloid (AML) and 10% of pediatric acute lymphoid (ALL) leukemia. More than 25 different reciprocal chromosomal translocations, with an 11q23 breakpoint, fuse the MLL gene (also named ALL-1, HRX and Htrx1) to a second partner gene. These leukemias have poor prognosis and frequently have a monocytic, lymphoid or biphenotypic (myeloid and lymphoid) antigen expression in blast cells. Approximately 20-30% of patients diagnosed as having adult de novo, AML have normal chromosomes by metaphase analysis and the majority of these patients have good prognosis. With the use of reverse transcriptase-polymerase chain reaction (RT-PCR) technique and Southern blot analysis, we found that seven of 34 such patients (21%) had a tandem partial duplication of exons 2 to 6 or 2 to 8 of the MLL gene. These seven patients showed a median survival of 2.7 months, compared to a 6.8 months median survival for all other patients in the study. If confirmed on a large series of patients, our findings may help differentiate AML with normal karyotype and poor prognosis from those with normal karyotype and a more favorable prognosis.

Research Square (Research Square), Sep 29, 2021

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 bene cial 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 identi ed by a multidisciplinary tumor board who underwent palliative spine surgery. In addition, we examined neurological de cits; ambulation status; pathological fracture, collapse, and postoperative implant failure progress; and Barthel Index (BI). Results The average duration of ambulation was 3.75 ± 3.92 days after surgery. One case showed collapse and two showed progressions of paralysis. However, all patients had early ambulation after surgery, except for one patient who developed postoperative cerebral infarction. The BI scores showed an improving tendency; however, the difference before and after rehabilitation was not statistically signi cant. Conclusions We reviewed the recovery course of ambulation in patients with cervical spine metastases who underwent impairment-driven rehabilitation. Combined with surgery and early mobilization, this strategy may improve the QOL of patients with cancer and cervical spine metastasis.

Human Pathology, Dec 1, 1994

To clarify the characteristics of the extracellular matrix of chondroblastomas, six cases were st... more To clarify the characteristics of the extracellular matrix of chondroblastomas, six cases were studied under the electron microscope, with special reference to proteoglycans and calcium in the cellular areas. In ruthenium hexammine trichloride (RHT)-stained sections the matrix was observed to be composed of rounded or polygonal fine granules and unbanded thin filaments that appeared to link neighboring granules together. Treatment with potassium-pyroantimonate showed intracellular accumulation of precipitates, mainly localized within the cisternae of the rough endoplasmic reticulum as well as in the extracellular matrix. The presence of calcium in the precipitates was confirmed using x-ray energy dispersive analysis. These findings, similar to characteristic features observed in calcifying systems, support the theory that chondroblastomas are of chondrogenic origin.

Oncology Letters, Sep 3, 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.

Skeletal Radiology, Jul 6, 2018

Malignant granular cell tumors are an extremely rare, high-grade sarcoma with a schwannian phenot... more Malignant granular cell tumors are an extremely rare, high-grade sarcoma with a schwannian phenotype and are composed of malignant granular cells with cytoplasmic lysosomal inclusion. To date, 157 cases of malignant granular cell tumors have been reported. We report the first case of a malignant granular cell tumor arising from the digital nerve to the median nerve in the palm, and we review the 157 previously reported cases and summarize the clinical profile, treatment, and outcome of this tumor. The median age, tumor size, and follow-up periods were 51 years, 6 cm, and 24 months respectively. With respect to the oncological result, 53 patients (33.8%) had no evidence for disease, 31 (19.7%) were alive with the disease, and 51 (32.5%) died because of the disease. Our case report indicates that rare malignant tumors can arise from the digital nerve to the median nerve in the palm, an anatomical site that is usually affected by benign lesions. Exhaustive discussions between surgeons and pathologists are necessary for the treatment of this rare malignant tumor.

Journal of Receptors and Signal Transduction, Jul 4, 2018

Free fatty acid (FFA) receptors belong to a member of G-protein-coupled receptors. GPCR 120 (GPR1... more Free fatty acid (FFA) receptors belong to a member of G-protein-coupled receptors. GPCR 120 (GPR120) and GPR40 are identified as FFA receptors and activated via the binding of long-and medium-chain FFAs. The aim of this study was to assess the effects of GPR120 and GPR40 on cell motility and growth in breast cancer cells treated with tamoxifen (TAM). MCF-7 cells were continuously treated with TAM for approximately 6 months. The expression level of GPR40 gene was markedly higher in the long-term TAM treated (MCF-TAM) cells than in MCF-7 cells. In cell motility assay, MCF-TAM cells indicated the high cell motile activity, compared with MCF-7 cells. The cell motile activity of MCF-TAM cells was suppressed by a selective GPR40 antagonist, GW1100. To evaluate the effects of GPR40 on cell growth activity under estrogen-free conditions, cells were maintained in serum-free DMEM without phenol red for 2 days. In estrogen-free conditioned medium, the cell growth rate of MCF-TAM cells was significantly higher than that of MCF-7 cells. In addition, treatment of GW1100 reduced the cell growth rate of MCF-TAM cells. These results suggest that the cell motile and growth activities may be positively regulated through the induction of GPR40 by the long-term TAM treatment in MCF-7 cells.

International Journal of Molecular Sciences, Mar 24, 2023

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

Biochemical and Biophysical Research Communications, Sep 1, 2018

Lysophosphatidic acid (LPA) receptors (LPA 1 to LPA 6) regulate a variety of malignant properties... more Lysophosphatidic acid (LPA) receptors (LPA 1 to LPA 6) regulate a variety of malignant properties in cancer cells. In the present study, we investigated the roles of LPA receptors in the promotion of cellular functions during tumor progression in fibrosarcoma cells. To obtain long-term anticancer drug treated cells, human fibrosarcoma HT1080 cells were treated with methotrexate (MTX) and cisplatin (CDDP) for 6 months. LPAR2 and LPAR5 expressions were significantly higher in MTX-treated (HT-MTX) cells than in HT1080 cells. The cell motile and invasive activities of HT-MTX cells were significantly elevated compared with HT1080 cells. Although LPAR5 expression was increased in MTX and CDDP treated (HT-M-C) cells, no change of LPAR2 expression was observed. The cell motile and invasive activities of HT-M-C cells were lower than those of HT1080 cells. Moreover, to evaluate whether LPA receptors promote cell invasive activity, highly invasion (HT1080-M6) cells were established from HT1080 cells. The cell invasive activity of HT1080-M6 cells was approximately 4.5 times higher than HT1080 cell invasion. LPAR2 expression was markedly elevated in HT1080-M6 cells compared with HT1080 cells. The high cell invasion activity of HT1080-M6 cells was significantly suppressed by an antagonist of LPA 2 , H2L5186303. These results suggest that LPA 2 acts as a key regulator of malignant properties in HT1080 cells.

DOAJ (DOAJ: Directory of Open Access Journals), 2022

Oncology Letters, Jul 19, 2012

The β2-adrenergic receptor (β2AR) mediates the effects of chronic stress in several neoplasms, ho... more The β2-adrenergic receptor (β2AR) mediates the effects of chronic stress in several neoplasms, however, β2AR signaling is impaired by hypoxia in various tissues. While hypoxia is a common feature significant in the progression of solid tumors, little is known about the effect of hypoxia on β2AR signaling in the tumor microenvironment. Previously, it has been reported that the systemic administration of mesenchymal stem cells (MSCs) increased the engraftment and metastatic colonization of rat osteosarcoma (OS) cells. In the current study, the effect of MSCs on the hypoxia-induced desensitization of the β2AR in OS cells was investigated. Epinephrine, norepinephrine and isoproterenol increased the cellular proliferation of the rat OS cell line COS1NR and rat MSCs in a dose-dependent and β2AR antagonist-sensitive manner. While isoproterenol had significant proliferative effects on MSCs under normoxic and hypoxic conditions, COS1NR cells did not respond under hypoxic conditions. A sensitivity assay for the β2AR revealed that hypoxia impaired the sensitivity of COS1NR cells, whereas hypoxia did not affect MSCs. An immunoassay revealed no significant change in the expression of hypoxia-inducible factor-1α (HIF1α) in COS1NR cells, whilst an immunoassay demonstrated a 15% increase in MSCs following isoproterenol stimulation. In COS1NR cells co-cultured with MSCs under hypoxic conditions, isoproterenol caused a significant increase in proliferation and this effect was inhibited by an anti-interleukin (IL)-6 antibody. A tumor formation assay in syngeneic rats revealed that the systemic administration of MSCs enhances the growth of OS and the effect of MSCs was inhibited by IL-6 neutralization. In conclusion, MSCs are resistant to the hypoxia-induced desensitization to β2AR. Hypoxia caused a siginificant desensitization of the β2AR in COS1NR cells alone, whereas MSCs may support tumor progression through cellular interactions.

Journal of Receptors and Signal Transduction, Jul 4, 2018

Lysophosphatidic acid (LPA) is a simple biological lipid and mediates several biological function... more Lysophosphatidic acid (LPA) is a simple biological lipid and mediates several biological functions with LPA receptors (LPA 1 to LPA 6). In the present study, to assess whether LPA receptors promote cell-invasive activity of pancreatic cancer cells, highly invasion PANC-R9 cells were established from PANC-1 cells, using Matrigel-coated Cell Culture Insert. The cell-invasive activity of PANC-R9 cells was shown to be approximately 15 times higher than that of PANC-1 cells. LPAR1 expression level was markedly elevated in PANC-R9 cells in comparison with PANC-1 cells, while LPAR3 expression level was reduced. The cell-invasive activity of PANC-R9 cells was enhanced by LPA, but LPA had no impact on PANC-1 cell invasion. Before initiation of the cell invasion assay, PANC-R9 cells were pretreated with dioctanoylglycerol pyrophosphate (DGPP), an antagonist of LPA 1 /LPA 3. The invasive activity of PANC-R9 cells was markedly suppressed by DGPP. Autotaxin (ATX) is a key enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to LPA. ATX expression level was elevated in PANC-R9 cells compared with PANC-1 cells. In the presence of LPC, the cell motile activity of PANC-R9 cells was markedly stimulated. In contrast, LPC did not affect the cell motile activity of PANC-1 cells. PANC-R9 cell motility was inhibited by an ATX inhibitor, PF-8380. These results suggest that LPA signaling via LPA 1 is a potent molecular target for the regulation of tumor progression in PANC-1 cells.

Progress in rehabilitation medicine, 2016

Histopathology, Jan 28, 2021

Journal of Surgical Oncology

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

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.

in Vivo, 2008

2-Methoxyestradiol (2-ME) has been found to possess antitumor activity in vivo and in vitro. It h... more 2-Methoxyestradiol (2-ME) has been found to possess antitumor activity in vivo and in vitro. It has been suggested that 2-ME induces apoptosis resulting in G 2 /M arrest of tumor cells. In this study, the effect of 2-ME was evaluated in rat osteosarcoma and malignant fibrous histiocytoma (MFH) cell lines. 2-ME was used at final concentrations of 100 nM to 2 ÌM. The effect of 2-ME on cell growth was measured by the MTS assay. Induction of apoptosis and activation of caspase-3 were investigated along with apoptosis-related gene expression. The data showed that 2-ME significantly inhibited cell growth, inducing apoptosis. The activity of caspase-3 was increased at 20 h and 40 h in both cell lines. 2-ME induced p16 expression, which was possibly involved in the apoptotic process. These results suggested that the 2-ME-induced apoptosis of rat osteosarcoma and rat MFH cells was accompanied by caspase-3 activation through p16 induction.

Oncology Letters, Dec 6, 2021

Endosialin/CD248/tumor endothelial marker 1 is classified as a C-type lectin-like transmembrane r... more Endosialin/CD248/tumor endothelial marker 1 is classified as a C-type lectin-like transmembrane receptor, found on the plasma membrane of activated mesenchymal cells, which binds to fibronectin. Although endosialin is expressed at high levels in stem-like cells of sarcomas, its role has not been fully uncovered. The present study aimed to determine whether endosialin expression is associated with tumor progression and metastasis, and whether endosialin has the potential to act as a novel therapeutic target in osteosarcoma (OS) using MORAb-004/ontuxizumab, a humanized monoclonal antibody, which targets the type C lectin domain of endosialin. The results demonstrated that endosialin was highly expressed in OSs with metastatic disease. Furthermore, MORAb-004 had no cytostatic effect on OS cells in vitro and did not change the expression of stem cells and differentiation markers; however, it inhibited migration of OS cells. Taken together, these results suggest that endosialin may play a role in migration, and may be involved in the metastatic process of OSs. Furthermore, MORAb-004 reduces the motility of OS cells, and suppresses invasion and the development of metastatic lesions.

PubMed, May 1, 1996

Rearrangement of the MLL (myeloid-lymphoid or mixed-lineage leukemia) gene through a reciprocal c... more Rearrangement of the MLL (myeloid-lymphoid or mixed-lineage leukemia) gene through a reciprocal chromosomal translocation is found in 5% of adult acute myeloid (AML) and 10% of pediatric acute lymphoid (ALL) leukemia. More than 25 different reciprocal chromosomal translocations, with an 11q23 breakpoint, fuse the MLL gene (also named ALL-1, HRX and Htrx1) to a second partner gene. These leukemias have poor prognosis and frequently have a monocytic, lymphoid or biphenotypic (myeloid and lymphoid) antigen expression in blast cells. Approximately 20-30% of patients diagnosed as having adult de novo, AML have normal chromosomes by metaphase analysis and the majority of these patients have good prognosis. With the use of reverse transcriptase-polymerase chain reaction (RT-PCR) technique and Southern blot analysis, we found that seven of 34 such patients (21%) had a tandem partial duplication of exons 2 to 6 or 2 to 8 of the MLL gene. These seven patients showed a median survival of 2.7 months, compared to a 6.8 months median survival for all other patients in the study. If confirmed on a large series of patients, our findings may help differentiate AML with normal karyotype and poor prognosis from those with normal karyotype and a more favorable prognosis.

Research Square (Research Square), Sep 29, 2021

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 bene cial 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 identi ed by a multidisciplinary tumor board who underwent palliative spine surgery. In addition, we examined neurological de cits; ambulation status; pathological fracture, collapse, and postoperative implant failure progress; and Barthel Index (BI). Results The average duration of ambulation was 3.75 ± 3.92 days after surgery. One case showed collapse and two showed progressions of paralysis. However, all patients had early ambulation after surgery, except for one patient who developed postoperative cerebral infarction. The BI scores showed an improving tendency; however, the difference before and after rehabilitation was not statistically signi cant. Conclusions We reviewed the recovery course of ambulation in patients with cervical spine metastases who underwent impairment-driven rehabilitation. Combined with surgery and early mobilization, this strategy may improve the QOL of patients with cancer and cervical spine metastasis.

Human Pathology, Dec 1, 1994

To clarify the characteristics of the extracellular matrix of chondroblastomas, six cases were st... more To clarify the characteristics of the extracellular matrix of chondroblastomas, six cases were studied under the electron microscope, with special reference to proteoglycans and calcium in the cellular areas. In ruthenium hexammine trichloride (RHT)-stained sections the matrix was observed to be composed of rounded or polygonal fine granules and unbanded thin filaments that appeared to link neighboring granules together. Treatment with potassium-pyroantimonate showed intracellular accumulation of precipitates, mainly localized within the cisternae of the rough endoplasmic reticulum as well as in the extracellular matrix. The presence of calcium in the precipitates was confirmed using x-ray energy dispersive analysis. These findings, similar to characteristic features observed in calcifying systems, support the theory that chondroblastomas are of chondrogenic origin.

Oncology Letters, Sep 3, 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.

Skeletal Radiology, Jul 6, 2018

Malignant granular cell tumors are an extremely rare, high-grade sarcoma with a schwannian phenot... more Malignant granular cell tumors are an extremely rare, high-grade sarcoma with a schwannian phenotype and are composed of malignant granular cells with cytoplasmic lysosomal inclusion. To date, 157 cases of malignant granular cell tumors have been reported. We report the first case of a malignant granular cell tumor arising from the digital nerve to the median nerve in the palm, and we review the 157 previously reported cases and summarize the clinical profile, treatment, and outcome of this tumor. The median age, tumor size, and follow-up periods were 51 years, 6 cm, and 24 months respectively. With respect to the oncological result, 53 patients (33.8%) had no evidence for disease, 31 (19.7%) were alive with the disease, and 51 (32.5%) died because of the disease. Our case report indicates that rare malignant tumors can arise from the digital nerve to the median nerve in the palm, an anatomical site that is usually affected by benign lesions. Exhaustive discussions between surgeons and pathologists are necessary for the treatment of this rare malignant tumor.

Journal of Receptors and Signal Transduction, Jul 4, 2018

Free fatty acid (FFA) receptors belong to a member of G-protein-coupled receptors. GPCR 120 (GPR1... more Free fatty acid (FFA) receptors belong to a member of G-protein-coupled receptors. GPCR 120 (GPR120) and GPR40 are identified as FFA receptors and activated via the binding of long-and medium-chain FFAs. The aim of this study was to assess the effects of GPR120 and GPR40 on cell motility and growth in breast cancer cells treated with tamoxifen (TAM). MCF-7 cells were continuously treated with TAM for approximately 6 months. The expression level of GPR40 gene was markedly higher in the long-term TAM treated (MCF-TAM) cells than in MCF-7 cells. In cell motility assay, MCF-TAM cells indicated the high cell motile activity, compared with MCF-7 cells. The cell motile activity of MCF-TAM cells was suppressed by a selective GPR40 antagonist, GW1100. To evaluate the effects of GPR40 on cell growth activity under estrogen-free conditions, cells were maintained in serum-free DMEM without phenol red for 2 days. In estrogen-free conditioned medium, the cell growth rate of MCF-TAM cells was significantly higher than that of MCF-7 cells. In addition, treatment of GW1100 reduced the cell growth rate of MCF-TAM cells. These results suggest that the cell motile and growth activities may be positively regulated through the induction of GPR40 by the long-term TAM treatment in MCF-7 cells.

International Journal of Molecular Sciences, Mar 24, 2023

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

Biochemical and Biophysical Research Communications, Sep 1, 2018

Lysophosphatidic acid (LPA) receptors (LPA 1 to LPA 6) regulate a variety of malignant properties... more Lysophosphatidic acid (LPA) receptors (LPA 1 to LPA 6) regulate a variety of malignant properties in cancer cells. In the present study, we investigated the roles of LPA receptors in the promotion of cellular functions during tumor progression in fibrosarcoma cells. To obtain long-term anticancer drug treated cells, human fibrosarcoma HT1080 cells were treated with methotrexate (MTX) and cisplatin (CDDP) for 6 months. LPAR2 and LPAR5 expressions were significantly higher in MTX-treated (HT-MTX) cells than in HT1080 cells. The cell motile and invasive activities of HT-MTX cells were significantly elevated compared with HT1080 cells. Although LPAR5 expression was increased in MTX and CDDP treated (HT-M-C) cells, no change of LPAR2 expression was observed. The cell motile and invasive activities of HT-M-C cells were lower than those of HT1080 cells. Moreover, to evaluate whether LPA receptors promote cell invasive activity, highly invasion (HT1080-M6) cells were established from HT1080 cells. The cell invasive activity of HT1080-M6 cells was approximately 4.5 times higher than HT1080 cell invasion. LPAR2 expression was markedly elevated in HT1080-M6 cells compared with HT1080 cells. The high cell invasion activity of HT1080-M6 cells was significantly suppressed by an antagonist of LPA 2 , H2L5186303. These results suggest that LPA 2 acts as a key regulator of malignant properties in HT1080 cells.

DOAJ (DOAJ: Directory of Open Access Journals), 2022

Oncology Letters, Jul 19, 2012

The β2-adrenergic receptor (β2AR) mediates the effects of chronic stress in several neoplasms, ho... more The β2-adrenergic receptor (β2AR) mediates the effects of chronic stress in several neoplasms, however, β2AR signaling is impaired by hypoxia in various tissues. While hypoxia is a common feature significant in the progression of solid tumors, little is known about the effect of hypoxia on β2AR signaling in the tumor microenvironment. Previously, it has been reported that the systemic administration of mesenchymal stem cells (MSCs) increased the engraftment and metastatic colonization of rat osteosarcoma (OS) cells. In the current study, the effect of MSCs on the hypoxia-induced desensitization of the β2AR in OS cells was investigated. Epinephrine, norepinephrine and isoproterenol increased the cellular proliferation of the rat OS cell line COS1NR and rat MSCs in a dose-dependent and β2AR antagonist-sensitive manner. While isoproterenol had significant proliferative effects on MSCs under normoxic and hypoxic conditions, COS1NR cells did not respond under hypoxic conditions. A sensitivity assay for the β2AR revealed that hypoxia impaired the sensitivity of COS1NR cells, whereas hypoxia did not affect MSCs. An immunoassay revealed no significant change in the expression of hypoxia-inducible factor-1α (HIF1α) in COS1NR cells, whilst an immunoassay demonstrated a 15% increase in MSCs following isoproterenol stimulation. In COS1NR cells co-cultured with MSCs under hypoxic conditions, isoproterenol caused a significant increase in proliferation and this effect was inhibited by an anti-interleukin (IL)-6 antibody. A tumor formation assay in syngeneic rats revealed that the systemic administration of MSCs enhances the growth of OS and the effect of MSCs was inhibited by IL-6 neutralization. In conclusion, MSCs are resistant to the hypoxia-induced desensitization to β2AR. Hypoxia caused a siginificant desensitization of the β2AR in COS1NR cells alone, whereas MSCs may support tumor progression through cellular interactions.

Journal of Receptors and Signal Transduction, Jul 4, 2018

Lysophosphatidic acid (LPA) is a simple biological lipid and mediates several biological function... more Lysophosphatidic acid (LPA) is a simple biological lipid and mediates several biological functions with LPA receptors (LPA 1 to LPA 6). In the present study, to assess whether LPA receptors promote cell-invasive activity of pancreatic cancer cells, highly invasion PANC-R9 cells were established from PANC-1 cells, using Matrigel-coated Cell Culture Insert. The cell-invasive activity of PANC-R9 cells was shown to be approximately 15 times higher than that of PANC-1 cells. LPAR1 expression level was markedly elevated in PANC-R9 cells in comparison with PANC-1 cells, while LPAR3 expression level was reduced. The cell-invasive activity of PANC-R9 cells was enhanced by LPA, but LPA had no impact on PANC-1 cell invasion. Before initiation of the cell invasion assay, PANC-R9 cells were pretreated with dioctanoylglycerol pyrophosphate (DGPP), an antagonist of LPA 1 /LPA 3. The invasive activity of PANC-R9 cells was markedly suppressed by DGPP. Autotaxin (ATX) is a key enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to LPA. ATX expression level was elevated in PANC-R9 cells compared with PANC-1 cells. In the presence of LPC, the cell motile activity of PANC-R9 cells was markedly stimulated. In contrast, LPC did not affect the cell motile activity of PANC-1 cells. PANC-R9 cell motility was inhibited by an ATX inhibitor, PF-8380. These results suggest that LPA signaling via LPA 1 is a potent molecular target for the regulation of tumor progression in PANC-1 cells.

Progress in rehabilitation medicine, 2016

Histopathology, Jan 28, 2021

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