Editorial

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Open AccessEditorial

State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan

by Junichi Yamaguchi, Eric di Luccio and Takaaki Hirotsu

Biomedicines 2023, 11(11), 2905; https://doi.org/10.3390/biomedicines11112905 - 26 Oct 2023

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Early cancer detection is key to improving patient survival and quality of life and reducing cancer treatments’ financial burden [...] Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

Research

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13 pages, 2830 KiB

Open AccessArticle

Hemoglobin β Expression Is Associated with Poor Prognosis in Clear Cell Renal Cell Carcinoma

by Yuta Kurota, Yuji Takeda, Osamu Ichiyanagi, Shinichi Saitoh, Hiromi Ito, Sei Naito, Hironobu Asao and Norihiko Tsuchiya

Biomedicines 2023, 11(5), 1330; https://doi.org/10.3390/biomedicines11051330 - 30 Apr 2023

Cited by 3 | Viewed by 1882

Abstract

Background: The regulation of the redox balance in the tumor microenvironment is thought to be an adaptive response of tumor cells to hypoxic environments. In recent years, it has been reported that the hemoglobin β-chain (HBB), which is involved in scavenging reactive oxygen [...] Read more.

Background: The regulation of the redox balance in the tumor microenvironment is thought to be an adaptive response of tumor cells to hypoxic environments. In recent years, it has been reported that the hemoglobin β-chain (HBB), which is involved in scavenging reactive oxygen species (ROS), is expressed in several carcinomas. However, the relationship between HBB expression and the prognosis of renal cell carcinoma (RCC) remains unclear. Methods: HBB expression was immunohistochemically analyzed in 203 nonmetastatic clear cell RCC (ccRCC) cases. Cell proliferation, invasion, and ROS production were measured in ccRCC cell lines treated with HBB-specific siRNA. Results: The prognosis of HBB-positive patients was worse than that of HBB-negative patients. Cell proliferation and invasion were inhibited, and ROS production was increased by treatment with HBB-specific siRNA. Oxidative stress increased HBB expression in cells exposed to H₂O₂. Conclusions: HBB expression in ccRCC contributes to cancer cell proliferation by suppressing ROS production under hypoxic conditions. Taken together with clinical results and in vitro experiments, HBB expression may serve as a new prognostic biomarker for RCC in the future. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

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13 pages, 1463 KiB

Open AccessArticle

Initial Myeloid Cell Status Is Associated with Clinical Outcomes of Renal Cell Carcinoma

by Saima Sabrina, Yuji Takeda, Tomoyuki Kato, Sei Naito, Hiromi Ito, Yuki Takai, Masaki Ushijima, Takafumi Narisawa, Hidenori Kanno, Toshihiko Sakurai, Shinichi Saitoh, Akemi Araki, Norihiko Tsuchiya and Hironobu Asao

Biomedicines 2023, 11(5), 1296; https://doi.org/10.3390/biomedicines11051296 - 27 Apr 2023

Cited by 1 | Viewed by 1380

Abstract

The therapeutic outcome of immune checkpoint inhibition (ICI) can be improved through combination treatments with ICI therapy. Myeloid-derived suppressor cells (MDSCs) strongly suppress tumor immunity. MDSCs are a heterogeneous cell population, originating from the unusual differentiation of neutrophils/monocytes induced by environmental factors such [...] Read more.

The therapeutic outcome of immune checkpoint inhibition (ICI) can be improved through combination treatments with ICI therapy. Myeloid-derived suppressor cells (MDSCs) strongly suppress tumor immunity. MDSCs are a heterogeneous cell population, originating from the unusual differentiation of neutrophils/monocytes induced by environmental factors such as inflammation. The myeloid cell population consists of an indistinguishable mixture of various types of MDSCs and activated neutrophils/monocytes. In this study, we investigated whether the clinical outcomes of ICI therapy could be predicted by estimating the status of the myeloid cells, including MDSCs. Several MDSC indexes, such as glycosylphosphatidylinositol-anchored 80 kD protein (GPI-80), CD16, and latency-associated peptide-1 (LAP-1; transforming growth factor-β1 precursor), were analyzed via flow cytometry using peripheral blood derived from patients with advanced renal cell carcinoma (n = 51) immediately before and during the therapy. Elevated CD16 and LAP-1 expressions after the first treatment were associated with a poor response to ICI therapy. Immediately before ICI therapy, GPI-80 expression in neutrophils was significantly higher in patients with a complete response than in those with disease progression. This is the first study to demonstrate a relationship between the status of the myeloid cells during the initial phase of ICI therapy and clinical outcomes. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

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15 pages, 4401 KiB

Open AccessArticle

In Silico Identification of Genes Associated with Breast Cancer Progression and Prognosis and Novel Therapeutic Targets

by Shiro Uchida and Takashi Sugino

Biomedicines 2022, 10(11), 2995; https://doi.org/10.3390/biomedicines10112995 - 21 Nov 2022

Cited by 2 | Viewed by 2121

Abstract

Molecular mechanisms underlying breast cancer (BC) progression are complex and remain unclear. In this study, we used bioinformatic tools to identify genes associated with tumor progression mechanisms and novel therapeutic targets in BC. We identified genes with stepwise upregulated expression overlapping between the [...] Read more.

Molecular mechanisms underlying breast cancer (BC) progression are complex and remain unclear. In this study, we used bioinformatic tools to identify genes associated with tumor progression mechanisms and novel therapeutic targets in BC. We identified genes with stepwise upregulated expression overlapping between the T and N stages during BC progression using LinkedOmics. We compared the expression level of each gene in BC tissues with that in normal breast tissues and evaluated differences in expression in their intrinsic subtypes and their prognostic value using UALCAN and GEPIA2. We also investigated the dependency of BC cell lines on these genes and whether they are potential therapeutic targets using DepMap. SPDEF, TRIM3, ABCB9, HSPB1, RHBG, SPINT1, EPN3, LRFN2, and PRPH were found to be involved in BC progression. High expression of ABCB9 and SPINT1 was associated with a poor prognosis. SPDEF, TRIM3, ABCB9, RHBG, SPINT1, and PRPH were found to be essential for survival in some BC cell lines (gene effect score < −0.5). PRPH was newly discovered to be involved in the progression of BC and the growth and survival of BC cell lines. Hence, SPDEF, TRIM3, ABCB9, RHBG, SPINT1, and PRPH may serve as novel potential therapeutic targets in BC. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

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13 pages, 792 KiB

Open AccessArticle

The Endometriotic Neoplasm Algorithm for Risk Assessment (e-NARA) Index Sheds Light on the Discrimination of Endometriosis-Associated Ovarian Cancer from Ovarian Endometrioma

by Naoki Kawahara, Ryuji Kawaguchi, Tomoka Maehana, Shoichiro Yamanaka, Yuki Yamada, Hiroshi Kobayashi and Fuminori Kimura

Biomedicines 2022, 10(11), 2683; https://doi.org/10.3390/biomedicines10112683 - 24 Oct 2022

Cited by 3 | Viewed by 1325

Abstract

Background: Magnetic resonance (MR) relaxometry provides a noninvasive tool to discriminate endometriosis-associated ovarian cancer (EAOC) from ovarian endometrioma (OE) with high accuracy. However, this method has a limitation in discriminating malignancy in clinical use because the R2 value depends on the device manufacturer [...] Read more.

Background: Magnetic resonance (MR) relaxometry provides a noninvasive tool to discriminate endometriosis-associated ovarian cancer (EAOC) from ovarian endometrioma (OE) with high accuracy. However, this method has a limitation in discriminating malignancy in clinical use because the R2 value depends on the device manufacturer and repeated imaging is unrealistic. The current study aimed to reassess the diagnostic accuracy of MR relaxometry and investigate a more powerful tool to distinguish EAOC from OE. Methods: This retrospective study was conducted at our institution from December, 2012, to May, 2022. A total of 150 patients were included in this study. Patients with benign ovarian tumors (n = 108) mainly received laparoscopic surgery, and cases with suspected malignancy (n = 42) underwent laparotomy. Information from a chart review of the patients’ medical records was collected. Results: A multiple regression analysis revealed that the age, the tumor diameter, and the R2 value were independent malignant predicting factors. The endometriotic neoplasm algorithm for risk assessment (e-NARA) index provided high accuracy (sensitivity, 85.7%; specificity, 87.0%) to discriminate EAOC from OE. Conclusions: The e-NARA index is a reliable tool to assess the probability of malignant transformation of endometrioma. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

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8 pages, 220 KiB

Open AccessEditor’s ChoiceArticle

Predictive Risk Factors Associated with Severe Radiation-Induced Mucositis in Nasopharyngeal or Oropharyngeal Cancer Patients: A Retrospective Study

by Yumiko Kawashita, Sakiko Soutome, Masahiro Umeda and Toshiyuki Saito

Biomedicines 2022, 10(10), 2661; https://doi.org/10.3390/biomedicines10102661 - 21 Oct 2022

Cited by 5 | Viewed by 1782

Abstract

Radiation-induced mucositis in head and neck cancer patients generates difficulties in eating and swallowing, and may influence treatment tolerance, compliance, and quality of life. However, predictive factors have not been studied in detail. Thus, the aim of this study was to describe the [...] Read more.

Radiation-induced mucositis in head and neck cancer patients generates difficulties in eating and swallowing, and may influence treatment tolerance, compliance, and quality of life. However, predictive factors have not been studied in detail. Thus, the aim of this study was to describe the association between pre-radiotherapy clinical factors and the incidence of severe radiation-induced mucositis in nasopharyngeal or oropharyngeal cancer patients. This retrospective study included all patients with definitive radiotherapy or chemoradiotherapy for nasopharyngeal or oropharyngeal cancer between July 2011 and June 2021 in a single center. The eligibility criteria included patients who received oral management during radiotherapy. Exclusion criteria was patients who received postoperative radiotherapy. The data were acquired from the medical records of patients. One hundred patients were included in this retrospective study. Grade 3 radiation-induced mucositis occurred in 47 patients (47%). Lymphocyte count was significantly associated with grade 3 mucositis (OR = 0.40; 95% CI = 0.19–0.86; p = 0.018). It is suggested that pre-radiation lower lymphocyte counts are a predictive risk factor for severe mucositis in patients who undergo definitive radiotherapy or chemoradiotherapy for nasopharyngeal or oropharyngeal cancer Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

Review

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13 pages, 1220 KiB

Open AccessReview

Mint3 as a Potential Target for Cooling Down HIF-1α-Mediated Inflammation and Cancer Aggressiveness

by Noritaka Tanaka and Takeharu Sakamoto

Biomedicines 2023, 11(2), 549; https://doi.org/10.3390/biomedicines11020549 - 14 Feb 2023

Cited by 4 | Viewed by 1876

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a crucial role in cells adapting to a low-oxygen environment by facilitating a switch from oxygen-dependent ATP production to glycolysis. Mediated by membrane type-1 matrix metalloproteinase (MT1-MMP) expression, Munc-18-1 interacting protein 3 (Mint3) binds [...] Read more.

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a crucial role in cells adapting to a low-oxygen environment by facilitating a switch from oxygen-dependent ATP production to glycolysis. Mediated by membrane type-1 matrix metalloproteinase (MT1-MMP) expression, Munc-18-1 interacting protein 3 (Mint3) binds to the factor inhibiting HIF-1 (FIH-1) and inhibits its suppressive effect, leading to HIF-1α activation. Defects in Mint3 generally lead to improved acute inflammation, which is regulated by HIF-1α and subsequent glycolysis, as well as the suppression of the proliferation and metastasis of cancer cells directly through its expression in cancer cells and indirectly through its expression in macrophages or fibroblasts associated with cancer. Mint3 in inflammatory monocytes enhances the chemotaxis into metastatic sites and the production of vascular endothelial growth factors, which leads to the expression of E-selectin at the metastatic sites and the extravasation of cancer cells. Fibroblasts express L1 cell adhesion molecules in a Mint3-dependent manner and enhance integrin-mediated cancer progression. In pancreatic cancer cells, Mint3 directly promotes cancer progression. Naphthofluorescein, a Mint3 inhibitor, can disrupt the interaction between FIH-1 and Mint3 and potently suppress Mint3-mediated inflammation, cancer progression, and metastasis without causing marked adverse effects. In this review, we will introduce the potential of Mint3 as a therapeutic target for inflammatory diseases and cancers. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

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11 pages, 7965 KiB

Open AccessReview

C. elegans as a Powerful Tool for Cancer Screening

by Eric di Luccio, Masayo Morishita and Takaaki Hirotsu

Biomedicines 2022, 10(10), 2371; https://doi.org/10.3390/biomedicines10102371 - 23 Sep 2022

Cited by 7 | Viewed by 3573

Abstract

Regular cancer screening is critical for early cancer detection. Cancer screening tends to be burdensome, invasive, and expensive, especially for a comprehensive multi-organ check. Improving the rate and effectiveness of routine cancer screenings remain a challenge in health care. Multi-cancer early detection (MCED) [...] Read more.

Regular cancer screening is critical for early cancer detection. Cancer screening tends to be burdensome, invasive, and expensive, especially for a comprehensive multi-organ check. Improving the rate and effectiveness of routine cancer screenings remain a challenge in health care. Multi-cancer early detection (MCED) is an exciting concept and a potentially effective solution for addressing current issues with routine cancer screening. In recent years, several technologies have matured for MCED, such as identifying cell-free tumor DNA in blood or using organisms such as Caenorhabditis elegans as a tool for early cancer detection. In Japan, N-NOSE is a commercially available multi-cancer detection test based on the chemotaxis of C. elegans using a urine sample showing 87.5% sensitivity and 90.2% specificity. In this review, we focus on using C. elegans as a powerful biosensor for universal cancer screening. We review N-NOSE clinical research results, spotlighting it as an effective primary cancer screening test. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

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15 pages, 2367 KiB

Open AccessReview

RNA Modification in Inflammatory Bowel Diseases

by Mika Nakayama, Yuki Ozato, Yoshiko Tsuji, Yasuko Arao, Chihiro Otsuka, Yumiko Hamano, Genzo Sumi, Ken Ofusa, Shizuka Uchida, Andrea Vecchione and Hideshi Ishii

Biomedicines 2022, 10(7), 1695; https://doi.org/10.3390/biomedicines10071695 - 13 Jul 2022

Cited by 3 | Viewed by 2337

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by damage to the intestinal mucosa, which is caused by a combination of factors. These include genetic and epigenetic alterations, environmental influence, microorganism interactions, and immune conditions. Some populations with IBD show a [...] Read more.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by damage to the intestinal mucosa, which is caused by a combination of factors. These include genetic and epigenetic alterations, environmental influence, microorganism interactions, and immune conditions. Some populations with IBD show a cancer-prone phenotype. Recent studies have provided insight into the involvement of RNA modifications in the specific pathogenesis of IBD through regulation of RNA biology in epithelial and immune cells. Studies of several RNA modification-targeting reagents have shown preferable outcomes in patients with colitis. Here, we note a new awareness of RNA modification in the targeting of IBD and related diseases, which will contribute to early diagnosis, disease monitoring, and possible control by innovative therapeutic approaches. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

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19 pages, 2206 KiB

Open AccessEditor’s ChoiceReview

Brain Cancer Chemotherapy through a Delivery System across the Blood-Brain Barrier into the Brain Based on Receptor-Mediated Transcytosis Using Monoclonal Antibody Conjugates

by Toshihiko Tashima

Biomedicines 2022, 10(7), 1597; https://doi.org/10.3390/biomedicines10071597 - 05 Jul 2022

Cited by 13 | Viewed by 4196

Abstract

Advances in pharmacotherapy have brought extraordinary benefits to humanity. However, unmet medical needs in patients remain, particularly in the treatment of central nervous system (CNS) diseases and cancers. CNS drug delivery into the brain across the endothelium is difficult due to the blood-brain [...] Read more.

Advances in pharmacotherapy have brought extraordinary benefits to humanity. However, unmet medical needs in patients remain, particularly in the treatment of central nervous system (CNS) diseases and cancers. CNS drug delivery into the brain across the endothelium is difficult due to the blood-brain barrier (BBB), which is composed mainly of tight junctions and efflux transporters, such as multiple drug resistance 1 (MDR1) (P-glycoprotein). On the other hand, the development of anti-cancer drugs is a challenging task due to their frequent off-target side effects and the complicated mechanisms of cancer pathogenesis and progression. Brain cancer treatment options are surgery, radiation therapy, and chemotherapy. It is difficult to remove all tumor cells, even by surgical removal after a craniotomy. Accordingly, innovative brain cancer drugs are needed. Currently, antibody (Ab) drugs that show high therapeutic effects are often used clinically. Furthermore, antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan, an anti-HER2 (human epidermal receptor 2) ADC with low-molecular cancer drugs through the suitable linker, have been developed. In the case of trastuzumab deruxtecan, it is internalized into cancer cells across the membrane via receptor-mediated endocytosis. Moreover, it is reported that drug delivery into the brain across the BBB was carried out via receptor-mediated transcytosis (RMT), using anti-receptor Abs as a vector against the transferrin receptor (TfR) or insulin receptor (InsR). Thus, anti-TfR ADCs with cancer drugs are promising brain cancer agents due to their precise distribution and low side effects. In this review, I introduce the implementations and potential of brain cancer drug delivery into the brain across the BBB, based on RMT using ADCs. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

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16 pages, 16632 KiB

Open AccessReview

EpisomiR, a New Family of miRNAs, and Its Possible Roles in Human Diseases

by Yasuko Arao, Mika Nakayama, Yoshiko Tsuji, Yumiko Hamano, Chihiro Otsuka, Andrea Vecchione, Ken Ofusa and Hideshi Ishii

Biomedicines 2022, 10(6), 1280; https://doi.org/10.3390/biomedicines10061280 - 30 May 2022

Cited by 5 | Viewed by 1991

Abstract

MicroRNAs (miRNAs) are synthesized through a canonical pathway and play a role in human diseases, such as cancers and cardiovascular, neurodegenerative, psychiatric, and chronic inflammatory diseases. The development of sequencing technologies has enabled the identification of variations in noncoding miRNAs. These miRNA variants, [...] Read more.

MicroRNAs (miRNAs) are synthesized through a canonical pathway and play a role in human diseases, such as cancers and cardiovascular, neurodegenerative, psychiatric, and chronic inflammatory diseases. The development of sequencing technologies has enabled the identification of variations in noncoding miRNAs. These miRNA variants, called isomiRs, are generated through a non-canonical pathway, by several enzymes that alter the length and sequence of miRNAs. The isomiR family is, now, expanding further to include episomiRs, which are miRNAs with different modifications. Since recent findings have shown that isomiRs reflect the cell-specific biological function of miRNAs, knowledge about episomiRs and isomiRs can, possibly, contribute to the optimization of diagnosis and therapeutic technology for precision medicine. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Biology, Biodiagnostics and Therapeutics in Japan)

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