Browsing by Author "Ogawa, Kazuhiko"

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    Exploring the Tumor-Suppressing Potential of PSCA in Pancreatic Ductal Adenocarcinoma
    (MDPI, 2023-10-10) Li, Kexin; Huo, Qingji; Minami, Kazumasa; Tamari, Keisuke; Ogawa, Kazuhiko; Na, Sungsoo; Fishel, Melissa L.; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates. We explored an innovative therapeutic approach by leveraging prognostic oncogenic markers. Instead of inhibiting these marker genes, we harnessed their tumor-modifying potential in the extracellular domain. Surprisingly, many of the proteins highly expressed in PDAC, which is linked to poor survival, exhibited tumor-suppressing qualities in the extracellular environment. For instance, prostate stem cell antigens (PSCA), associated with reduced survival, acted as tumor suppressors when introduced extracellularly. We performed in vitro assays to assess the proliferation and migration and evaluated the tumor-modifying capacity of extracellular factors from peripheral blood mononuclear cells (PBMCs) in PDAC tissues. Molecular docking analysis, immunoprecipitation, Western blotting, and RNA interference were employed to study the regulatory mechanism. Extracellular PSCA recombinant protein notably curtailed the viability, motility, and transwell invasion of PDAC cells. Its anti-PDAC effects were partially mediated by Mesothelin (MSLN), another highly expressed tumor-associated antigen in PDAC. The anti-tumor effects of extracellular PSCA complemented those of chemotherapeutic agents like Irinotecan, 5-Fluorouracil, and Oxaliplatin. PSCA expression increased in a conditioned medium derived from PBMCs and T lymphocytes. This study unveils the paradoxical anti-PDAC potential of PSCA, hinting at the dual roles of oncoproteins like PSCA in PDAC suppression.
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    Intensity-modulated radiation therapy dose verification using fluence and portal imaging device
    (2016) Sumida, Iori; Yamaguchi, Hajime; Das, Indra J.; Kizaki, Hisao; Aboshi, Keiko; Tsujii, Mari; Yamada, Yuji; Suzuki, Osamu; Seo, Yuji; Isohashi, Fumiaki; Ogawa, Kazuhiko; Department of Radiation Oncology, IU School of Medicine
    Patient-specific quality assurance for intensity-modulated radiation therapy (IMRT) dose verification is essential. The aim of this study is to provide a new method based on the relative error distribution by comparing the fluence map from the treatment planning system (TPS) and the incident fluence deconvolved from the electronic portal imaging device (EPID) images. This method is validated for 10 head and neck IMRT cases. The fluence map of each beam was exported from the TPS and EPID images of the treatment beams were acquired. Measured EPID images were deconvolved to the incident fluence with proper corrections. The relative error distribution between the TPS fluence map and the incident fluence from the EPID was created. This was also created for a 2D diode array detector. The absolute point dose was measured with an ionization chamber, and the dose distribution was measured by a radiochromic film. In three cases, MLC leaf positions were intentionally changed to create the dose error as much as 5% against the planned dose and our fluence-based method was tested using gamma index. Absolute errors between the predicted dose of 2D diode detector and of our method and measure­ments were 1.26% ± 0.65% and 0.78% ± 0.81% respectively. The gamma passing rate (3% global / 3 mm) of the TPS was higher than that of the 2D diode detector (p< 0.02), and lower than that of the EPID (p < 0.04). The gamma passing rate (2% global / 2 mm) of the TPS was higher than that of the 2D diode detector, while the gamma passing rate of the TPS was lower than that of EPID (p < 0.02). For three modified plans, the predicted dose errors against the measured dose were 1.10%, 2.14%, and -0.87%. The predicted dose distributions from the EPID were well matched to the measurements. Our fluence-based method provides very accurate dosimetry for IMRT patients. The method is simple and can be adapted to any clinic for complex cases.
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    Osteocyte-Driven Downregulation of Snail Restrains Effects of Drd2 Inhibitors on Mammary Tumor Cells
    (American Association for Cancer Research, 2018-07-15) Liu, Shengzhi; Fan, Yao; Chen, Andy; Jalali, Aydin; Minami, Kazumasa; Ogawa, Kazuhiko; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    While bone is a frequent target of breast cancer-associated metastasis, little is known about the effects of tumor-bone interactions on the efficacy of tumor-suppressing agents. Here we examined the effect of two FDA-approved dopamine modulators, fluphenazine and trifluoperazine, on mammary tumor cells, osteoclasts, osteoblasts, and osteocytes. These agents suppressed proliferation and migration of mammary tumor cells chiefly by antagonizing dopamine receptor D2 and reduced bone resorption by downregulating nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1). Three-dimensional spheroid formation assays revealed that tumor cells have high affinity to osteocytes and type I collagen, and interactions with osteocytes as well as administration of fluphenazine and trifluoperazine downregulated Snail and suppressed migratory behaviors. Unlike the inhibitory action of fluphenazine and trifluoperazine on tumor growth, tumor-osteocyte interactions stimulated tumor proliferation by upregulating NFκB and Akt. In the bone microenvironment, osteocytes downregulated Snail and acted as an attractant as well as a stimulant to mammary tumor cells. These results demonstrate that tumor-osteocyte interactions strengthen dopamine receptor-mediated suppression of tumor migration but weaken its inhibition of tumor proliferation in the osteocyte-rich bone microenvironment.Significance: These findings provide novel insight into the cellular cross-talk in the bone microevironment and the effects of dopamine modulators on mammary tumor cells and osteocytes. Cancer Res; 78(14); 3865-76. ©2018 AACR.
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    Proteomes from AMPK-inhibited peripheral blood mononuclear cells suppress the progression of breast cancer and bone metastasis
    (Ivyspring, 2023-02-05) Li, Kexin; Sun, Xun; Minami, Kazumasa; Tamari, Keisuke; Ogawa, Kazuhiko; Li, Hudie; Ma, Hailan; Zhou, Meng; Na, Sungsoo; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Background: During a developmental process, embryos employ varying tactics to remove unwanted cells. Using a procedure analogous to some of the embryonic cells, we generated a tumor-eliminating conditioned medium (CM) from AMPK-inhibited lymphocytes and monocytes in peripheral blood mononuclear cells (PBMCs). Methods: AMPK signaling was inhibited by the application of a pharmacological agent, Dorsomorphin, and the therapeutic effects of their conditioned medium (CM) were evaluated using in vitro cell cultures, ex vivo breast cancer tissues, and a mouse model of mammary tumors and tumor-induced osteolysis. The regulatory mechanism was evaluated using mass spectrometry-based proteomics, Western blotting, immunoprecipitation, gene overexpression, and RNA interference. Results: While AMPK signaling acted mostly anti-tumorigenic, we paradoxically inhibited it to build induced tumor-suppressing cells and their tumor-eliminating CM. In a mouse model of breast cancer, the application of AMPK-inhibited lymphocyte-derived CM reduced mammary tumors additively to a chemotherapeutic agent, Taxol. It also prevented bone loss in the tumor-bearing tibia. Furthermore, the application of CM from the patient-derived peripheral blood diminished ex vivo breast cancer tissues isolated from the same patients. Notably, proteins enriched in CM included Moesin (MSN), Enolase 1 (ENO1), and polyA-binding protein 1 (PABPC1), which are considered tumorigenic in many types of cancer. The tumor-suppressing actions of MSN and ENO1 were at least in part mediated by Metadherin (Mtdh), which is known to promote metastatic seeding. Conclusion: We demonstrated that PBMCs can be used to generate tumor-suppressive proteomes, and extracellular tumor-suppressing proteins such as MSN, ENO1, and PABPC1 are converted from tumor-promoting factors inside cancer cells. The results support the possibility of developing autologous blood-based therapy, in which tumor-suppressing proteins are enriched in engineered PBMC-derived CM by the inhibition of AMPK signaling.
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    Suppression of osteosarcoma progression by engineered lymphocyte-derived proteomes
    (Elsevier, 2022-08-28) Li, Kexin; Sun, Xun; Li, Hudie; Ma, Hailan; Zhou, Meng; Minami, Kazumasa; Tamari, Keisuke; Ogawa, Kazuhiko; Pandya, Pankita H.; Saadatzadeh, M. Reza; Kacena, Melissa A.; Pollok, Karen E.; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Cancer cells tend to develop resistance to chemotherapy and enhance aggressiveness. A counterintuitive approach is to tame aggressiveness by an agent that acts opposite to chemotherapeutic agents. Based on this strategy, induced tumor-suppressing cells (iTSCs) have been generated from tumor cells and mesenchymal stem cells. Here, we examined the possibility of generating iTSCs from lymphocytes by activating PKA signaling for suppressing the progression of osteosarcoma (OS). While lymphocyte-derived CM did not present anti-tumor capabilities, the activation of PKA converted them into iTSCs. Inhibiting PKA conversely generated tumor-promotive secretomes. In a mouse model, PKA-activated CM suppressed tumor-induced bone destruction. Proteomics analysis revealed that moesin (MSN) and calreticulin (Calr), which are highly expressed intracellular proteins in many cancers, were enriched in PKA-activated CM, and they acted as extracellular tumor suppressors through CD44, CD47, and CD91. The study presented a unique option for cancer treatment by generating iTSCs that secret tumor-suppressive proteins such as MSN and Calr. We envision that identifying these tumor suppressors and predicting their binding partners such as CD44, which is an FDA-approved oncogenic target to be inhibited, may contribute to developing targeted protein therapy.
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    The inhibition of pancreatic cancer progression by K-Ras-overexpressing mesenchymal stem cell-derived secretomes
    (Springer Nature, 2023-09-12) Huo, Qingji; Li, Kexin; Sun, Xun; Zhuang, Adam; Minami, Kazumasa; Tamari, Keisuke; Ogawa, Kazuhiko; Fishel, Melissa L.; Li, Bai‑Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival. To explore an uncharted function of K-Ras proto-oncogene, K-Ras was activated in mesenchymal stem cells (MSCs) and the effects of MSC conditioned medium (CM) on PDAC were examined. Overexpression of K-Ras elevated PI3K signaling in MSCs, and K-Ras/PI3K-activated MSC-derived CM reduced the proliferation and migration of tumor cells, as well as the growth of ex vivo freshly isolated human PDAC cultures. CM's anti-tumor capability was additive with Gemcitabine, a commonly used chemotherapeutic drug in the treatment of PDAC. The systemic administration of CM in a mouse model suppressed the colonization of PDAC in the lung. MSC CM was enriched with Moesin (MSN), which acted as an extracellular tumor-suppressing protein by interacting with CD44. Tumor-suppressive CM was also generated by PKA-activated peripheral blood mononuclear cells. Collectively, this study demonstrated that MSC CM can be engineered to act as a tumor-suppressive agent by activating K-Ras and PI3K, and the MSN-CD44 regulatory axis is in part responsible for this potential unconventional option in the treatment of PDAC.