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15 pages, 3064 KiB

Open AccessArticle

Role of Extracellular High-Mobility Group Box-1 as a Therapeutic Target of Gastric Cancer

by Wataru Takaki, Hirotaka Konishi, Daiki Matsubara, Katsutoshi Shoda, Tomohiro Arita, Satoshi Kataoka, Jun Shibamoto, Hirotaka Furuke, Kazuya Takabatake, Hiroki Shimizu, Shuhei Komatsu, Atsushi Shiozaki, Takeshi Kubota, Kazuma Okamoto and Eigo Otsuji

Int. J. Mol. Sci. 2022, 23(6), 3264; https://doi.org/10.3390/ijms23063264 - 17 Mar 2022

Cited by 6 | Viewed by 2429

Abstract

Background: High-mobility group box-1 (HMGB1) is involved in the tumorigenesis and metastasis of various cancers. The present study investigated the roles of extracellular HMGB1 in the progression of gastric cancer (GC) and the therapeutic effects of recombinant human soluble thrombomodulin (rTM) targeting HMGB1. [...] Read more.

Background: High-mobility group box-1 (HMGB1) is involved in the tumorigenesis and metastasis of various cancers. The present study investigated the roles of extracellular HMGB1 in the progression of gastric cancer (GC) and the therapeutic effects of recombinant human soluble thrombomodulin (rTM) targeting HMGB1. Methods: The effects of extracellular HMGB1 and rTM on GC cells were assessed using proliferation and Transwell assays. Their effects on local tumor growth and metastasis were evaluated using subcutaneous tumor and liver metastasis mouse models, respectively. Plasma HMGB1 concentrations in GC patients were measured using ELISA. The relationships between plasma HMGB1 concentrations and the prognosis and clinicopathological factors of patients were also investigated. Results: GC proliferation, migration, and invasion abilities were promoted by increases in extracellular HMGB1 concentrations and alleviated by rTM. In the subcutaneous tumor model, local tumor growth was promoted by the addition of rhHMGB1 and alleviated by rTM. Similar changes occurred in the liver metastasis model. Recurrence-free survival (p < 0.01) and overall survival (p = 0.01) were significantly worse in patients with high plasma HMGB1 concentrations. Conclusion: Plasma HMGB1 concentrations are a prognostic marker in GC patients. Extracellular HMGB1 promotes cancer progression and has potential as a novel treatment target in GC cells for rTM. Full article

(This article belongs to the Special Issue Gastrointestinal Cancers: Molecular Pathophysiology, Novel Biomarkers and Therapeutic Approaches)

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13 pages, 9075 KiB

Open AccessArticle

Identifying the Metabolic Signatures of PPARD-Overexpressing Gastric Tumors

by Shivanand Pudakalakatti, Mark Titus, José S. Enriquez, Sumankalai Ramachandran, Niki M. Zacharias, Imad Shureiqi, Yi Liu, James C. Yao, Xiangsheng Zuo and Pratip K. Bhattacharya

Int. J. Mol. Sci. 2022, 23(3), 1645; https://doi.org/10.3390/ijms23031645 - 31 Jan 2022

Cited by 6 | Viewed by 3442

Abstract

Peroxisome proliferator-activated receptor delta (PPARD) is a nuclear receptor known to play an essential role in regulation of cell metabolism, cell proliferation, inflammation, and tumorigenesis in normal and cancer cells. Recently, we found that a newly generated villin-PPARD mouse model, in which PPARD [...] Read more.

Peroxisome proliferator-activated receptor delta (PPARD) is a nuclear receptor known to play an essential role in regulation of cell metabolism, cell proliferation, inflammation, and tumorigenesis in normal and cancer cells. Recently, we found that a newly generated villin-PPARD mouse model, in which PPARD is overexpressed in villin-positive gastric progenitor cells, demonstrated spontaneous development of large, invasive gastric tumors as the mice aged. However, the role of PPARD in regulation of downstream metabolism in normal gastric and tumor cells is elusive. The aim of the present study was to find PPARD-regulated downstream metabolic changes and to determine the potential significance of those changes to gastric tumorigenesis in mice. Hyperpolarized [1-¹³C] pyruvate magnetic resonance spectroscopy, nuclear magnetic resonance spectroscopy, and liquid chromatography-mass spectrometry were employed for metabolic profiling to determine the PPARD-regulated metabolite changes in PPARD mice at different ages during the development of gastric cancer, and the changes were compared to corresponding wild-type mice. Nuclear magnetic resonance spectroscopy-based metabolomic screening results showed higher levels of inosine monophosphate (p = 0.0054), uracil (p = 0.0205), phenylalanine (p = 0.017), glycine (p = 0.014), and isocitrate (p = 0.029) and lower levels of inosine (p = 0.0188) in 55-week-old PPARD mice than in 55-week-old wild-type mice. As the PPARD mice aged from 10 weeks to 35 weeks and 55 weeks, we observed significant changes in levels of the metabolites inosine monophosphate (p = 0.0054), adenosine monophosphate (p = 0.009), UDP-glucose (p = 0.0006), and oxypurinol (p = 0.039). Hyperpolarized [1-¹³C] pyruvate magnetic resonance spectroscopy performed to measure lactate flux in live 10-week-old PPARD mice with no gastric tumors and 35-week-old PPARD mice with gastric tumors did not reveal a significant difference in the ratio of lactate to total pyruvate plus lactate, indicating that this PPARD-induced spontaneous gastric tumor development does not require glycolysis as the main source of fuel for tumorigenesis. Liquid chromatography-mass spectrometry-based measurement of fatty acid levels showed lower linoleic acid, palmitic acid, oleic acid, and steric acid levels in 55-week-old PPARD mice than in 10-week-old PPARD mice, supporting fatty acid oxidation as a bioenergy source for PPARD-expressing gastric tumors. Full article

(This article belongs to the Special Issue Gastrointestinal Cancers: Molecular Pathophysiology, Novel Biomarkers and Therapeutic Approaches)

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13 pages, 6491 KiB

Open AccessArticle

BRAF Mutation Is Associated with Hyperplastic Polyp-Associated Gastric Cancer

by Rina Fujiwara-Tani, Ayaka Okamoto, Hiroyuki Katsuragawa, Hitoshi Ohmori, Kiyomu Fujii, Shiori Mori, Shingo Kishi, Takamitsu Sasaki, Chie Nakashima, Isao Kawahara, Yudai Hojo, Yukiko Nishiguchi, Takuya Mori, Takeshi Mizumoto, Kenta Nagai, Yi Luo and Hiroki Kuniyasu

Int. J. Mol. Sci. 2021, 22(23), 12724; https://doi.org/10.3390/ijms222312724 - 25 Nov 2021

Cited by 4 | Viewed by 3302

Abstract

Gastric hyperplastic polyps (GHP) are frequently found to be benign polyps and have been considered to have a low carcinogenic potential. The characteristics of the hyperplastic polyp-associated gastric cancer (HPAGC) remain unclear. Therefore, we analyzed samples from 102 GHP patients and identified 20 [...] Read more.

Gastric hyperplastic polyps (GHP) are frequently found to be benign polyps and have been considered to have a low carcinogenic potential. The characteristics of the hyperplastic polyp-associated gastric cancer (HPAGC) remain unclear. Therefore, we analyzed samples from 102 GHP patients and identified 20 low-grade atypical GHPs (19.6%), 7 high-grade atypical GHPs (6.9%), and 5 intramucosal cancer samples (4.9%). GHP atypia was more common in the elderly and increased with increasing polyp size. In particular, polyps larger than 1 cm were associated with a higher grade and cancer. Furthermore, mucus production decreased with increasing atypia. Although no correlation was found between atypia and Helicobacter pylori infection or intestinal metaplasia, enhanced proliferative ability (Ki-67) did correlate with atypia, as did nuclear 8-hydroxy-2’-deoxyguanosine levels. Interestingly, 4-hydroxynonenal levels in granulation tissue and the area ratio of granulation tissue within polyps also correlated with GHP atypia. In five cases of HPAGC, three cases exhibited caudal type homeobox transcription factor (CDX2)-positive cells and a mixed mucin phenotype, which is considered to be related to H. pylori infection. By contrast, two cases were CDX2 negative, with a gastric mucin phenotype, and H. pylori infection was not observed in the tumor or the surrounding mucosa. In these cases, a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation (V600E) was detected. All cancer samples showed high stemness and p53 protein accumulation, but no KRAS mutations. The molecular and phenotypic characteristics of the cases characterized by BRAF mutations may represent a novel subtype of HPAGC, reflecting a conserved pathway to oncogenesis that does not involve H. pylori infection. These findings are worthy of further investigation in a large-scale study with a substantial cohort of HPAGC patients to establish their clinical significance. Full article

(This article belongs to the Special Issue Gastrointestinal Cancers: Molecular Pathophysiology, Novel Biomarkers and Therapeutic Approaches)

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13 pages, 2145 KiB

Open AccessArticle

Enhancement of Anti-Tumoral Immunity by β-Casomorphin-7 Inhibits Cancer Development and Metastasis of Colorectal Cancer

by Shiori Mori, Rina Fujiwara-Tani, Shingo Kishi, Takamitsu Sasaki, Hitoshi Ohmori, Kei Goto, Chie Nakashima, Yukiko Nishiguchi, Isao Kawahara, Yi Luo and Hiroki Kuniyasu

Int. J. Mol. Sci. 2021, 22(15), 8232; https://doi.org/10.3390/ijms22158232 - 30 Jul 2021

Cited by 14 | Viewed by 2974

Abstract

β-Casomorphin-7 (BCM) is a degradation product of β-casein, a milk component, and has been suggested to affect the immune system. However, its effect on mucosal immunity, especially anti-tumor immunity, in cancer-bearing individuals is not clear. We investigated the effects of BCM on lymphocytes [...] Read more.

β-Casomorphin-7 (BCM) is a degradation product of β-casein, a milk component, and has been suggested to affect the immune system. However, its effect on mucosal immunity, especially anti-tumor immunity, in cancer-bearing individuals is not clear. We investigated the effects of BCM on lymphocytes using an in vitro system comprising mouse splenocytes, a mouse colorectal carcinogenesis model, and a mouse orthotopic colorectal cancer model. Treatment of mouse splenocytes with BCM in vitro reduced numbers of cluster of differentiation (CD) 20⁺ B cells, CD4⁺ T cells, and regulatory T cells (Tregs), and increased CD8⁺ T cells. Administration of BCM and the CD10 inhibitor thiorphan (TOP) to mice resulted in similar alterations in the lymphocyte subsets in the spleen and intestinal mucosa. BCM was degraded in a concentration- and time-dependent manner by the neutral endopeptidase CD10, and the formed BCM degradation product did not affect the lymphocyte counts. Furthermore, degradation was completely suppressed by TOP. In the azoxymethane mouse colorectal carcinogenesis model, the incidence of aberrant crypt foci, adenoma, and adenocarcinoma was reduced by co-treatment with BCM and TOP. Furthermore, when CT26 mouse colon cancer cells were inoculated into the cecum of syngeneic BALB/c mice and concurrently treated with BCM and TOP, infiltration of CD8⁺ T cells was promoted, and tumor growth and liver metastasis were suppressed. These results suggest that by suppressing the BCM degradation system, the anti-tumor effect of BCM is enhanced and it can suppress the development and progression of colorectal cancer. Full article

(This article belongs to the Special Issue Gastrointestinal Cancers: Molecular Pathophysiology, Novel Biomarkers and Therapeutic Approaches)

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13 pages, 4587 KiB

Open AccessArticle

Combinatorial Treatment of Tinzaparin and Chemotherapy Can Induce a Significant Antitumor Effect in Pancreatic Cancer

by Panagiotis Sarantis, Alexandros Bokas, Adriana Papadimitropoulou, Evangelos Koustas, Stamatios Theocharis, Pavlos Papakotoulas, Dimitrios Schizas, Alexandros Papalampros, Evangelos Felekouras, Athanasios G. Papavassiliou and Michalis V. Karamouzis

Int. J. Mol. Sci. 2021, 22(13), 7053; https://doi.org/10.3390/ijms22137053 - 30 Jun 2021

Cited by 14 | Viewed by 2733

Abstract

Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that [...] Read more.

Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis; hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds. Full article

(This article belongs to the Special Issue Gastrointestinal Cancers: Molecular Pathophysiology, Novel Biomarkers and Therapeutic Approaches)

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Review

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12 pages, 916 KiB

Open AccessReview

Gastrointestinal Bleeding Due to NOACs Use: Exploring the Molecular Mechanisms

by Angela Saviano, Mattia Brigida, Carmine Petruzziello, Marcello Candelli, Maurizio Gabrielli and Veronica Ojetti

Int. J. Mol. Sci. 2022, 23(22), 13955; https://doi.org/10.3390/ijms232213955 - 12 Nov 2022

Cited by 12 | Viewed by 4187

Abstract

Novel oral anticoagulants (NOACs) are drugs approved for the prevention and treatment of many thromboembolic cardiovascular conditions as a safer alternative to warfarin. We reviewed studies published in PubMed^®, UpToDate^®, Web of Science^®, and Cochrane^® about [...] Read more.

Novel oral anticoagulants (NOACs) are drugs approved for the prevention and treatment of many thromboembolic cardiovascular conditions as a safer alternative to warfarin. We reviewed studies published in PubMed^®, UpToDate^®, Web of Science^®, and Cochrane^® about NOACs’ risks and benefits in patients requiring anticoagulation, with a focus on gastrointestinal bleeding and on molecular and pathophysiological mechanisms underlying the risk of bleeding in patients treated with them. Apixaban resulted in a lower rate of gastrointestinal bleeding compared to dabigatran and rivaroxaban. However, data reported that gastrointestinal bleeding in patients treated with NOACs was less severe compared to warfarin. Studies show promising results on the increased and widespread use of NOACs in patients who require anticoagulation (for example—in case of atrial fibrillation or high risk of venous thromboembolism), reporting an overall lower risk of major bleeding events. The profile of NOACs was more effective and secure compared to warfarin, but a more careful medical prescription is required in patients who are at high risk of gastrointestinal bleeding. Full article

(This article belongs to the Special Issue Gastrointestinal Cancers: Molecular Pathophysiology, Novel Biomarkers and Therapeutic Approaches)

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16 pages, 644 KiB

Open AccessReview

Tissue-Based Markers as a Tool to Assess Response to Neoadjuvant Radiotherapy in Rectal Cancer—Systematic Review

by Edgaras Smolskas, Goda Mikulskytė, Ernestas Sileika, Kestutis Suziedelis and Audrius Dulskas

Int. J. Mol. Sci. 2022, 23(11), 6040; https://doi.org/10.3390/ijms23116040 - 27 May 2022

Cited by 5 | Viewed by 2493

Abstract

According to current guidelines, the current treatment for locally advanced rectal cancer is neoadjuvant therapy, followed by a total mesorectal excision. However, radiosensitivity tends to differ among patients due to tumor heterogeneity, making it difficult to predict the possible outcomes of the neoadjuvant [...] Read more.

According to current guidelines, the current treatment for locally advanced rectal cancer is neoadjuvant therapy, followed by a total mesorectal excision. However, radiosensitivity tends to differ among patients due to tumor heterogeneity, making it difficult to predict the possible outcomes of the neoadjuvant therapy. This review aims to investigate different types of tissue-based biomarkers and their capability of predicting tumor response to neoadjuvant therapy in patients with locally advanced rectal cancer. We identified 169 abstracts in NCBI PubMed, selected 48 reports considered to meet inclusion criteria and performed this systematic review. Multiple classes of molecular biomarkers, such as proteins, DNA, micro-RNA or tumor immune microenvironment, were studied as potential predictors for rectal cancer response; nonetheless, no literature to date has provided enough sufficient evidence for any of them to be introduced into clinical practice. Full article

(This article belongs to the Special Issue Gastrointestinal Cancers: Molecular Pathophysiology, Novel Biomarkers and Therapeutic Approaches)

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50 pages, 689 KiB

Open AccessReview

Novel Diagnostic Biomarkers in Colorectal Cancer

by Aneta L. Zygulska and Piotr Pierzchalski

Int. J. Mol. Sci. 2022, 23(2), 852; https://doi.org/10.3390/ijms23020852 - 13 Jan 2022

Cited by 113 | Viewed by 14647

Abstract

Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used [...] Read more.

Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used for risk stratification and early detection, which might prolong overall survival. Nowadays, the widespread use of semi-invasive endoscopic methods and feacal blood tests characterised by suboptimal accuracy of diagnostic results has led to the detection of cases at later stages. New molecular noninvasive tests based on the detection of CRC alterations seem to be more sensitive and specific then the current methods. Therefore, research aiming at identifying molecular markers, such as DNA, RNA and proteins, would improve survival rates and contribute to the development of personalized medicine. The identification of “ideal” diagnostic biomarkers, having high sensitivity and specificity, being safe, cheap and easy to measure, remains a challenge. The purpose of this review is to discuss recent advances in novel diagnostic biomarkers for tumor tissue, blood and stool samples in CRC patients. Full article

(This article belongs to the Special Issue Gastrointestinal Cancers: Molecular Pathophysiology, Novel Biomarkers and Therapeutic Approaches)

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