Editorial

4 pages, 184 KiB

Open AccessEditorial

by Masa-Aki Shibata and Kohei Taniguchi

Int. J. Mol. Sci. 2023, 24(8), 7123; https://doi.org/10.3390/ijms24087123 - 12 Apr 2023

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Cancer metastasis is a common biological phenomenon observed in malignant tumors that can lead to death in affected individuals [...] Full article

(This article belongs to the Special Issue Metastasis Inhibition)

Research

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20 pages, 4666 KiB

Open AccessArticle

NKX6.1 Represses Tumorigenesis, Metastasis, and Chemoresistance in Colorectal Cancer

by Hsin-Hua Chung, Chun-Te Lee, Je-Ming Hu, Yu-Ching Chou, Ya-Wen Lin and Yu-Lueng Shih

Int. J. Mol. Sci. 2020, 21(14), 5106; https://doi.org/10.3390/ijms21145106 - 19 Jul 2020

Cited by 12 | Viewed by 2578

Abstract

Accumulating evidence suggests that NKX6.1 (NK homeobox 1) plays a role in various types of cancer. In our previous studies, we identified NKX6.1 hypermethylation as a promising marker and demonstrated that the NKX6.1 gene functions as a metastasis suppressor through the epigenetic regulation [...] Read more.

Accumulating evidence suggests that NKX6.1 (NK homeobox 1) plays a role in various types of cancer. In our previous studies, we identified NKX6.1 hypermethylation as a promising marker and demonstrated that the NKX6.1 gene functions as a metastasis suppressor through the epigenetic regulation of the epithelial-to-mesenchymal transition (EMT) in cervical cancer. More recently, we have demonstrated that NKX6.1 methylation is related to the chemotherapy response in colorectal cancer (CRC). Nevertheless, the biological function of NKX6.1 in the tumorigenesis of CRC remains unclear. In this study, we showed that NKX6.1 suppresses tumorigenic and metastatic ability both in vitro and in vivo. NKX6.1 represses cell invasion partly through the modulation of EMT. The overexpression of NKX6.1 enhances chemosensitivity in CRC cells. To further explore how NKX6.1 exerts its tumor-suppressive function, we used RNA sequencing technology for comprehensive analysis. The results showed that differentially expressed genes (DEGs) were mainly related to cell migration, response to drug, transcription factor activity, and growth factor activity, suggesting that these DEGs are involved in the function of NKX6.1 suppressing cancer invasion and metastasis. Our results demonstrated that NKX6.1 functions as a tumor suppressor partly by repressing EMT and enhancing chemosensitivity in CRC, making it a potential therapeutic target. Full article

(This article belongs to the Special Issue Metastasis Inhibition)

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17 pages, 1915 KiB

Open AccessArticle

High Expression of microRNA-143 is Associated with Favorable Tumor Immune Microenvironment and Better Survival in Estrogen Receptor Positive Breast Cancer

by Yoshihisa Tokumaru, Mariko Asaoka, Masanori Oshi, Eriko Katsuta, Li Yan, Sumana Narayanan, Nobuhiko Sugito, Nobuhisa Matsuhashi, Manabu Futamura, Yukihiro Akao, Kazuhiro Yoshida and Kazuaki Takabe

Int. J. Mol. Sci. 2020, 21(9), 3213; https://doi.org/10.3390/ijms21093213 - 01 May 2020

Cited by 39 | Viewed by 3751

Abstract

microRNA-143 (miR-143) is a well-known tumor suppressive microRNA that exhibits anti-tumoral function by targeting KRAS signaling pathways in various malignancies. We hypothesized that miR-143 suppresses breast cancer progression by targeting KRAS and its effector molecules. We further hypothesized that high expression of miR-143 [...] Read more.

microRNA-143 (miR-143) is a well-known tumor suppressive microRNA that exhibits anti-tumoral function by targeting KRAS signaling pathways in various malignancies. We hypothesized that miR-143 suppresses breast cancer progression by targeting KRAS and its effector molecules. We further hypothesized that high expression of miR-143 is associated with a favorable tumor immune microenvironment of estrogen receptor (ER)-positive breast cancer patients which result in improved survival. Two major publicly available breast cancer cohorts; The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used. The miR-143 high expression group was associated with increased infiltration of anti-cancer immune cells and decreased pro-cancer immune cells, as well as enrichment of the genes relating to T helper (Th1) cells resulting in improved overall survival (OS) in ER-positive breast cancer patients. To the best of our knowledge, this is the first study to demonstrate that high expression of miR-143 in cancer cells associates with a favorable tumor immune microenvironment, upregulation of anti-cancer immune cells, and suppression of the pro-cancer immune cells, associating with better survival of the breast cancer patients. Full article

(This article belongs to the Special Issue Metastasis Inhibition)

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7 pages, 2323 KiB

Open AccessArticle

Convolutional Neural Network Can Recognize Drug Resistance of Single Cancer Cells

by Kiminori Yanagisawa, Masayasu Toratani, Ayumu Asai, Masamitsu Konno, Hirohiko Niioka, Tsunekazu Mizushima, Taroh Satoh, Jun Miyake, Kazuhiko Ogawa, Andrea Vecchione, Yuichiro Doki, Hidetoshi Eguchi and Hideshi Ishii

Int. J. Mol. Sci. 2020, 21(9), 3166; https://doi.org/10.3390/ijms21093166 - 30 Apr 2020

Cited by 12 | Viewed by 3234

Abstract

It is known that single or isolated tumor cells enter cancer patients’ circulatory systems. These circulating tumor cells (CTCs) are thought to be an effective tool for diagnosing cancer malignancy. However, handling CTC samples and evaluating CTC sequence analysis results are challenging. Recently, [...] Read more.

It is known that single or isolated tumor cells enter cancer patients’ circulatory systems. These circulating tumor cells (CTCs) are thought to be an effective tool for diagnosing cancer malignancy. However, handling CTC samples and evaluating CTC sequence analysis results are challenging. Recently, the convolutional neural network (CNN) model, a type of deep learning model, has been increasingly adopted for medical image analyses. However, it is controversial whether cell characteristics can be identified at the single-cell level by using machine learning methods. This study intends to verify whether an AI system could classify the sensitivity of anticancer drugs, based on cell morphology during culture. We constructed a CNN based on the VGG16 model that could predict the efficiency of antitumor drugs at the single-cell level. The machine learning revealed that our model could identify the effects of antitumor drugs with ~0.80 accuracies. Our results show that, in the future, realizing precision medicine to identify effective antitumor drugs for individual patients may be possible by extracting CTCs from blood and performing classification by using an AI system. Full article

(This article belongs to the Special Issue Metastasis Inhibition)

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15 pages, 2129 KiB

Open AccessArticle

High Expression of miR-34a Associated with Less Aggressive Cancer Biology but Not with Survival in Breast Cancer

by Yoshihisa Tokumaru, Eriko Katsuta, Masanori Oshi, Judith C. Sporn, Li Yan, Lan Le, Nobuhisa Matsuhashi, Manabu Futamura, Yukihiro Akao, Kazuhiro Yoshida and Kazuaki Takabe

Int. J. Mol. Sci. 2020, 21(9), 3045; https://doi.org/10.3390/ijms21093045 - 26 Apr 2020

Cited by 38 | Viewed by 3726

Abstract

Most breast cancer (BC) patients succumb to metastatic disease. MiR-34a is a well-known tumor suppressive microRNA which exerts its anti-cancer functions by playing a role in p53, apoptosis induction, and epithelial-mesenchymal transition (EMT) suppression. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and [...] Read more.

Most breast cancer (BC) patients succumb to metastatic disease. MiR-34a is a well-known tumor suppressive microRNA which exerts its anti-cancer functions by playing a role in p53, apoptosis induction, and epithelial-mesenchymal transition (EMT) suppression. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) cohorts were used to test our hypothesis that miR-34a high BCs translate to less aggressive cancer biology and better survival in large cohorts. There was no association between miR-34a expression levels and clinicopathological features of BC patients except for HER2 positivity. MiR-34a high expressing tumors were associated with lower Nottingham pathological grades and lower MKI67 expression. In agreement, high miR-34a tumors demonstrated lower GSVA scores of cell cycle and cell proliferation-related gene sets. High miR-34a tumors enriched the p53 pathway and apoptosis gene sets. Unexpectedly, high miR-34a tumors also associated with elevated EMT pathway score and ZEB1 and two expressions. MiR-34a expression did not associate with any distant metastasis. Further, high miR-34a tumors did not associate with better survival compared with miR-34a low tumors. In conclusion, the clinical relevance of miR-34a high expressing tumors was associated with suppressed cell proliferation, enhanced p53 pathway and apoptosis, but enhanced EMT and these findings did not reflect better survival outcomes in large BC patient cohorts. Full article

(This article belongs to the Special Issue Metastasis Inhibition)

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17 pages, 2187 KiB

Open AccessArticle

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

by Masanori Oshi, Hideo Takahashi, Yoshihisa Tokumaru, Li Yan, Omar M. Rashid, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe

Int. J. Mol. Sci. 2020, 21(8), 2921; https://doi.org/10.3390/ijms21082921 - 22 Apr 2020

Cited by 98 | Viewed by 5255

Abstract

The vast majority of breast cancer death is a result of metastasis. Thus, accurate identification of patients who are likely to have metastasis is expected to improve survival. The G2M checkpoint plays a critical role in cell cycle. We hypothesized that breast cancer [...] Read more.

The vast majority of breast cancer death is a result of metastasis. Thus, accurate identification of patients who are likely to have metastasis is expected to improve survival. The G2M checkpoint plays a critical role in cell cycle. We hypothesized that breast cancer tumors with high activity of G2M pathway genes are more aggressive and likely to metastasize. To test this, we used the single-sample gene set variation analysis method to calculate the score for the Hallmark G2M checkpoint pathway using gene expression data of a total of 4626 samples from 12 human breast cancer cohorts. As expected, a high G2M pathway score correlated with enriched tumor expression of other cell proliferation-related gene sets. The score was significantly associated with clinical aggressive features of tumors and patient survival in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Interestingly, a high G2M score of metastasis tumors was also significantly associated with worse survival. In primary as well as metastasis tumors with high scores, the infiltration of both pro- and anti-cancerous immune cells increased. Tumor G2M score was also associated with treatment response to systemic chemotherapy in ER-positive/HER2-negative cancer, and was predictive of response to cyclin-dependent kinase inhibition therapy. Full article

(This article belongs to the Special Issue Metastasis Inhibition)

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Review

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16 pages, 1273 KiB

Open AccessReview

Extracellular Vesicles in Cancer Metastasis: Potential as Therapeutic Targets and Materials

by Akiko Kogure, Yusuke Yoshioka and Takahiro Ochiya

Int. J. Mol. Sci. 2020, 21(12), 4463; https://doi.org/10.3390/ijms21124463 - 23 Jun 2020

Cited by 45 | Viewed by 4196

Abstract

The vast majority of cancer-related deaths are due to metastasis of the primary tumor that develops years to decades after apparent cures. However, it is difficult to effectively prevent or treat cancer metastasis. Recent studies have shown that communication between cancer cells and [...] Read more.

The vast majority of cancer-related deaths are due to metastasis of the primary tumor that develops years to decades after apparent cures. However, it is difficult to effectively prevent or treat cancer metastasis. Recent studies have shown that communication between cancer cells and surrounding cells enables cancer progression and metastasis. The comprehensive term “extracellular vesicles” (EVs) describes lipid bilayer vesicles that are secreted to outside cells; EVs are well-established mediators of cell-to-cell communication. EVs participate in cancer progression and metastasis by transferring bioactive molecules, such as proteins and RNAs, including microRNAs (miRNAs), between cancer and various cells in local and distant microenvironments. Clinically, EVs functioning as diagnostic biomarkers, therapeutic targets, or even as anticancer drug-delivery vehicles have been emphasized as a result of their unique biological and pathophysiological characteristics. The potential therapeutic effects of EVs in cancer treatment are rapidly emerging and represent a new and important area of research. This review focuses on the therapeutic potential of EVs and discusses their utility for the inhibition of cancer progression, including metastasis. Full article

(This article belongs to the Special Issue Metastasis Inhibition)

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15 pages, 2181 KiB

Open AccessReview

Role of Bone Targeting Agents in the Prevention of Bone Metastases from Breast Cancer

by Stella D’Oronzo, Erica Silvestris, Angelo Paradiso, Mauro Cives and Marco Tucci

Int. J. Mol. Sci. 2020, 21(8), 3022; https://doi.org/10.3390/ijms21083022 - 24 Apr 2020

Cited by 13 | Viewed by 4358

Abstract

Breast cancer (BC) is the most common malignancy in women worldwide and leads, in more than 70% of patients with advanced disease, to skeleton colonization and formation of bone metastases (BM). This condition implies a severe disability and deterioration of the quality of [...] Read more.

Breast cancer (BC) is the most common malignancy in women worldwide and leads, in more than 70% of patients with advanced disease, to skeleton colonization and formation of bone metastases (BM). This condition implies a severe disability and deterioration of the quality of life, with consequent additional social costs. In recent decades, several studies explored the role of agents acting within the bone microenvironment to counteract BM development, and several bone-targeting agents (BTAs) have been introduced in the clinical practice to manage bone lesions and reduce the risk of skeletal complications. However, long-term exposure to these agents is not free from potential toxicities and needs careful monitoring. In this context, the potential capability to prevent BM onset in selected BC patients, through the early administration of BTAs, has been explored by several researchers, with the belief that “prevention is better than cure” and that, ultimately, metastatic BC is an incurable condition. Here, we revised the mechanisms of BM development in BC as well as the strategies for selecting high-risk patients suitable for early BTA treatment. Full article

(This article belongs to the Special Issue Metastasis Inhibition)

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12 pages, 289 KiB

Open AccessReview

Brain Metastases in Lung Cancers with Emerging Targetable Fusion Drivers

by Aaron C. Tan, Malinda Itchins and Mustafa Khasraw

Int. J. Mol. Sci. 2020, 21(4), 1416; https://doi.org/10.3390/ijms21041416 - 19 Feb 2020

Cited by 22 | Viewed by 4154

Abstract

The management of non-small cell lung cancer (NSCLC) has transformed with the discovery of therapeutically tractable oncogenic drivers. In addition to activating driver mutations, gene fusions or rearrangements form a unique sub-class, with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 [...] Read more.

The management of non-small cell lung cancer (NSCLC) has transformed with the discovery of therapeutically tractable oncogenic drivers. In addition to activating driver mutations, gene fusions or rearrangements form a unique sub-class, with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) targeted agents approved as the standard of care in the first-line setting for advanced disease. There are a number of emerging fusion drivers, however, including neurotrophin kinase (NTRK), rearrangement during transfection (RET), and neuregulin 1 (NRG1) for which there are evolving high-impact systemic treatment options. Brain metastases are highly prevalent in NSCLC patients, with molecularly selected populations such as epidermal growth factor receptor (EGFR) mutant and ALK-rearranged tumors particularly brain tropic. Accordingly, there exists a substantial body of research pertaining to the understanding of brain metastases in such populations. Little is known, however, on the molecular mechanisms of brain metastases in those with other targetable fusion drivers in NSCLC. This review encompasses key areas including the biological underpinnings of brain metastases in fusion-driven lung cancers, the intracranial efficacy of novel systemic therapies, and future directions required to optimize the control and prevention of brain metastases. Full article

(This article belongs to the Special Issue Metastasis Inhibition)

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