Published papers

癌ゲノム医療の現場において、患者の語りを傾聴し、正しく状況を理解すべき職種として、看護師と並んで薬剤師が挙げられる。癌遺伝子外来での患者対応の実情、遺伝性腫瘍症候群について概説し、ゲノム医療における多職種連携の目指すべき姿について述べた。関与する医療者がそれぞれの立場で患者に必要な情報を伝える必要があり、その中でも薬剤師の関与は重要であると考えられた。

Pancreatic adenocarcinoma is a lethal disease that often develops a desmoplastic reaction in tumor stroma. In general, desmoplasia is thought to promote tumor growth. However, its molecular pathology and prognostic potential have not been fully investigated. Here, we investigate 26 cases of pancreatic ductal adenocarcinoma and examine the clinicopathological association between survival and expression levels of several molecular markers for stromal cells. These include alpha-smooth muscle actin (SMA) and platelet-derived growth factor (PDGF) receptor beta (PDGFR beta). Both are markers of activated fibroblasts or pancreatic stellate cells (PSCs) that play an important role in desmoplasia. The staining patterns of both molecular markers were not uniform, so we categorized them into 3 grades (high, middle, and low) according to intensity. Interestingly, Kaplan-Meier analysis revealed that higher expression of PDGFR beta matched shorter prognosis (p = 0.0287, log-rank test) as well as lymphatic invasion and lymph node metastasis, whereas SMA did not (p = 0.6122). Our results suggest the prognostic potential of cancer stroma via PDGF-B signaling. Regulation of PDGF-B-associated signaling crosstalk between cancer cells and stroma cells, therefore, may indicate a possible therapeutic target for desmoplastic malignant tumors such as pancreatic adenocarcinoma.

Nano drug delivery systems (nanoDDS) are a promising strategy for treatment of human tumors. As indicated by our previous work, the extent of pericyte-coverage of tumor vasculature is important to determining nanoDDS efficacy since intratumoral accumulation of nanoDDS is less in tumor models with pericyte-covered vasculature. Here we investigated the clinical relevance of our previous observations in animal models, by determining pericyte coverage using immunohistochemistry of smooth muscle actin (SMA) with CD34: a vascular endothelial marker, in human tumor tissue samples. The investigation revealed that tumor vasculature coverage by pericytes in pancreatic and diffuse-type gastric cancers was significantly greater than in ovarian, colon, and intestinal-type gastric cancers. The latter group of cancers is easier to treat clinically. These observations are consistent with our previous findings in animal models. On the basis of these findings we believe optimization of nanoDDS delivery should be done depend upon a clear understanding of the effects of pericyte vascular coverage.

Malignant pleural mesothelioma (MPM) is characterized by dissemination and aggressive growth in the thoracic cavity. Podoplanin (PDPN) is an established diagnostic marker for MPM, but the function of PDPN in MPM is not fully understood. The purpose of this study was to determine the pathogenetic function of PDPN in MPM. Forty-seven of 52 tumors (90%) from Japanese patients with MPM and 3/6 (50%) MPM cell lines tested positive for PDPN. Knocking down PDPN in PDPN-high expressing MPM cells resulted in decreased cell motility. In contrast, overexpression of PDPN in PDPN-low expressing MPM cells enhanced cell motility. PDPN stimulated motility was mediated by activation of the RhoA/ROCK pathway. Moreover, knocking down PDPN with short hairpin (sh) RNA in PDPN-high expressing MPM cells resulted in decreased development of a thoracic tumor in mice with severe combined immune deficiency (SCID). In sharp contrast, transfection of PDPN in PDPN-low expressing MPM cells resulted in an increase in the number of Ki-67-positive proliferating tumor cells and it promoted progression of a thoracic tumor in SCID mice. Interestingly, PDPN promoted focus formation invitro, and a low level of E-cadherin expression and YAP1 activation was observed in PDPN-high MPM tumors. These findings indicate that PDPN is a diagnostic marker as well as a pathogenetic regulator that promotes MPM progression by increasing cell motility and inducing focus formation. Therefore, PDPN might be a pathogenetic determinant of MPM dissemination and aggressive growth and may thus be an ideal therapeutic target.

The favorable prognosis of high-grade oligodendroglial tumor such as glioblastoma (GBM) with oligodendroglioma component (GBMO) has been suggested; however, the studies which examine the prognostic significance of oligodendroglial tumor were limited. In this study, we performed a histopathology-based reevaluation of 111 cases of high grade gliomas according to the latest World Health Organization (WHO), and compared the clinical outcomes between oligodendroglial tumors and pure astrocytic tumors. The survival analysis revealed that the patients with high grade oligodendroglial tumor including GBMO significantly indicated better prognosis compared to the patients with high grade pure astrocytic tumors (GBM and AA, anaplastic astrocytoma) as expected, and the obtained survival curves were almost identical to those from the patients with conventional Grade III or Grade IV tumors, respectively. Moreover, if the cases of oligodendroglial tumor were histopathologically excluded, the patients with AA exhibited extremely poor prognosis which was similar to that of GBM, suggesting that the histological identification of oligodendroglial tumor component, even partially, prescribe the prognosis of high grade glioma patients. This is the prominent report of retrospective clinicopathological analysis for high-grade gliomas throughout Grade III and IV, especially referring to the prognostic value of histological oligodendroglial tumor component; in addition, our results might offer an alternative aspect for the grading of high-grade astrocytic/oligodendroglial tumors.

Angiogenesis is a multi-step process that culminates in vascular maturation whereby nascent vessels stabilize to become functional, and mural cells play an essential role in this process. Recent studies have shown that mural cells in tumors also promote and maintain vascular integrity, with wide-reaching clinical implications including the regulation of tumor growth, metastases, and drug delivery. Various regulatory signaling pathways have been hitherto implicated, but whether regulation of Fas-dependent apoptotic mechanisms is involved has not yet been fully investigated. We first compared endothelial FAS staining in human pancreatic ductal adenocarcinomas and colon carcinomas and show that the latter, characterized by lower mural cell coverage of tumor vasculature, demonstrated higher expression of FAS than the former. Next, in an invitro coculture system of MS-1 and 10T1/2 cells as endothelial and mural cells respectively, we show that mural cells decreased endothelial Fas expression. Then, in an invivo model in which C26 colon carcinoma cells were inoculated together with MS-1 cells alone or with the further addition of 10T1/2 cells, we demonstrate that mural cells prevented hemorrhage. Finally, knockdown of endothelial Fas sufficiently recapitulated the protection against hemorrhage seen with the addition of mural cells. These results together suggest that regulation of endothelial Fas signaling is involved in the promotion of vascular integrity by mural cells in tumors.

JC virus (JCV) is a causative agent of progressive multifocal leukoencephalopathy (PML). Methyl CpG binding protein 2 (MeCP2) is a transcriptional control nuclear protein that is abundantly expressed in neurons. We previously observed that the MeCP2 protein is expressed in JCV large T antigen (TAg)-expressing glial cells in PML brains. To investigate the relationship between MeCP2 and JCV TAg, we examined the promoter activity and mRNA and protein expression levels of MeCP2 in JCV TAg-expressing cells. We found that JCV TAg enhances the promoter activity of MeCP2, but does not enhance the mRNA and protein levels of MeCP2. These results suggest that post-transcriptional mechanisms may play a role in MeCP2 expression.

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA-alkylating agent temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide-induced DNA damage due to elevated expression of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). Here, we show that upregulation of both MGMT and STAT3 was accompanied with acquisition of temozolomide resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or short hairpin RNA (shRNA) downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of interleukin (IL)-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis of 44 malignant glioma specimens showed significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (p-STAT3; P < 0.001, gamma = 0.58). Importantly, the levels of both MGMT and p-STAT3 were increased in the recurrence compared with the primary lesion in paired identical tumors of 12 cases. Finally, we showed that STAT3 inhibitor or STAT3 knockdown potentiated temozolomide efficacy in temozolomide-resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with temozolomide for patients with temozolomide-resistant GBM. Mol Cancer Ther; 11(6); 1289-99. (C)2012 AACR.

We reviewed the relationship between extent of resection and survival of patients with high-grade gliomas with special consideration of an oligodendroglial component.A retrospective review was performed on 160 adult patients with histological diagnosis of high-grade gliomas since 2000. All histological slides were categorized as high-grade astrocytomas or oligodendroglial tumors. Extent of resection was assessed by early post-operative magnetic resonance imaging and classified as complete resection, incomplete resection and biopsy. Measured outcomes were overall survival and progression-free survival. The independent association of extent of resection and survival was analyzed by the multivariate proportional hazard model adjusting for prognostic factors.The lesions were classified as high-grade astrocytomas in 93 patients and high-grade oligodendroglial tumors in 67 patients. In high-grade astrocytomas, the median survival after complete resection (n 36), incomplete resection (n 36) and biopsy (n 21) was 23.4, 15.3 and 12.6 months, respectively. Complete resection was independently associated with increased overall survival (P 0.001) and progression-free survival (P 0.002) compared with incomplete resection, while incomplete resection was not associated with survival benefit compared with biopsy by multivariate analysis. On the other hand, in high-grade oligodendroglial tumors, the majority of patients were still alive and there is no significant difference in the survival between complete resection (n 24) and incomplete resection (n 33), while even incomplete resection had a significantly longer overall survival (P 0.001) and progression-free survival (P 0.006) compared with biopsy (n 10).Maximal cytoreduction improves the survival of high-grade gliomas, although our data indicated that the impact of extent of resection in high-grade astrocytomas is different from that in high-grade oligodendroglial tumors.

Introduction: Most metastatic prostate cancers acquire the capacity for androgen-independent growth and become resistant to androgen deprivation therapy. A patient-focused treatment strategy is needed for aggressive castration-resistant prostate cancer. Case presentation: We report the case of a 62-year-old man who presented with prostatic adenocarcinoma who was treated by radiation and combined androgen blockade. After completion of first-line therapy, he was diagnosed with multiple metastatic castration-resistant prostate cancer in the lung. Second-line therapy with abiraterone acetate resulted in partial remission of the lung metastases. Thoracic surgery was performed to remove the single lung metastasis remaining. Next-generation sequencing of the specimens demonstrated homozygous loss of BRCA2. We note in this case a heterogeneous response to abiraterone acetate may be related to the somatic BRCA2 deletions. Conclusions: We present the first Japanese case of a metastatic abiraterone acetate-resistant castration-resistant prostate cancer accompanied by BRCA2 mutation.

INTRODUCTION: Genomic profiling provides useful information for diagnosis, treatment, and prognosis, and detection of certain defects, such as DNA repair gene aberrations or microsatellite instability, can possibly lead to optimal treatment, but this testing has not been widely used to inform prostate cancer treatment. CASE PRESENTATION: A 55-year-old man sequentially treated for prostate cancer was diagnosed as neuroendocrine prostate cancer from prostate specimens resected because of urinary retention. Subsequently, he received five cycles of platinum-based chemotherapy in total and responded well. We also performed next-generation sequencing of a sample from the prostate specimen and identified a breast cancer susceptibility gene mutation with Murine Double Minute 2 amplification and loss of heterozygosity in retinoblastoma 1. CONCLUSION: We report a neuroendocrine prostate cancer patient with Murine Double Minute 2 amplification who experienced an aggressive course and for whom platinum-based chemotherapy was effective, and one of the reasons for the good response might be the breast cancer susceptibility gene mutation.