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18 pages, 2805 KiB

Open AccessArticle

ICAM-1-suPAR-CD11b Axis Is a Novel Therapeutic Target for Metastatic Triple-Negative Breast Cancer

by Dong Li, Hami Hemati, Younhee Park, Rokana Taftaf, Youbin Zhang, Jinpeng Liu, Massimo Cristofanilli and Xia Liu

Cancers 2023, 15(10), 2734; https://doi.org/10.3390/cancers15102734 - 12 May 2023

Cited by 6 | Viewed by 2789

Abstract

Accumulating evidence demonstrates that circulating tumor cell (CTC) clusters have higher metastatic ability than single CTCs and negatively correlate with cancer patient outcomes. Along with homotypic CTC clusters, heterotypic CTC clusters (such as neutrophil–CTC clusters), which have been identified in both cancer mouse [...] Read more.

Accumulating evidence demonstrates that circulating tumor cell (CTC) clusters have higher metastatic ability than single CTCs and negatively correlate with cancer patient outcomes. Along with homotypic CTC clusters, heterotypic CTC clusters (such as neutrophil–CTC clusters), which have been identified in both cancer mouse models and cancer patients, lead to more efficient metastasis formation and worse patient outcomes. However, the mechanism by which neutrophils bind to CTCs remains elusive. In this study, we found that intercellular adhesion molecule-1 (ICAM-1) on triple-negative breast cancer (TNBC) cells and CD11b on neutrophils mediate tumor cell–neutrophil binding. Consequently, CD11b deficiency inhibited tumor cell–neutrophil binding and TNBC metastasis. Furthermore, CD11b mediated hydrogen peroxide (H₂O₂) production from neutrophils. Moreover, we found that ICAM-1 in TNBC cells promotes tumor cells to secrete suPAR, which functions as a chemoattractant for neutrophils. Knockdown of uPAR in ICAM-1⁺ TNBC cells reduced lung-infiltrating neutrophils and lung metastasis. Bioinformatics analysis confirmed that uPAR is highly expressed in TNBCs, which positively correlates with higher neutrophil infiltration and negatively correlates with breast cancer patient survival. Collectively, our findings provide new insight into how neutrophils bind to CTC to facilitate metastasis and discover a novel potential therapeutic strategy by blocking the ICAM-1-suPAR-CD11b axis to inhibit TNBC metastasis. Full article

(This article belongs to the Special Issue Targeting Cancer Metastasis (Volume II))

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21 pages, 1928 KiB

Open AccessArticle

The TLK1–MK5 Axis Regulates Motility, Invasion, and Metastasis of Prostate Cancer Cells

by Md Imtiaz Khalil and Arrigo De Benedetti

Cancers 2022, 14(23), 5728; https://doi.org/10.3390/cancers14235728 - 22 Nov 2022

Cited by 4 | Viewed by 2559

Abstract

Background: Metastatic dissemination of prostate cancer (PCa) accounts for the majority of PCa-related deaths. However, the exact mechanism of PCa cell spread is still unknown. We uncovered a novel interaction between two unrelated promotility factors, tousled-like kinase 1 (TLK1) and MAPK-activated protein [...] Read more.

Background: Metastatic dissemination of prostate cancer (PCa) accounts for the majority of PCa-related deaths. However, the exact mechanism of PCa cell spread is still unknown. We uncovered a novel interaction between two unrelated promotility factors, tousled-like kinase 1 (TLK1) and MAPK-activated protein kinase 5 (MK5), that initiates a signaling cascade promoting metastasis. In PCa, TLK1–MK5 signaling might be crucial, as androgen deprivation therapy (ADT) leads to increased expression of both TLK1 and MK5 in metastatic patients, but in this work, we directly investigated the motility, invasive, and metastatic capacity of PCa cells following impairment of the TLK1 > MK5 axis. Results: We conducted scratch wound repair and transwell invasion assays with LNCaP and PC3 cells to determine if TLK1 and MK5 can regulate motility and invasion. Both genetic depletion and pharmacologic inhibition of TLK1 and MK5 resulted in reduced migration and invasion through a Matrigel plug. We further elucidated the potential mechanisms underlying these effects and found that this is likely due to the reorganization of the actin fibers at lamellipodia and the focal adhesions network, in conjunction with increased expression of some MMPs that can affect penetration through the ECM. PC3, a highly metastatic cell line when assayed in xenografts, was further tested in a tail-vein injection/lung metastasis model, and we showed that, following inoculation, treatment with GLPG0259 (MK5 specific inhibitor) or J54 (TLK1 inhibitor) resulted in the lung tumor nodules being greatly diminished in number, and for J54, also in size. Conclusion: Our data support that the TLK1–MK5 axis is functionally involved in driving PCa cell metastasis and clinical aggressiveness; hence, disruption of this axis may inhibit the metastatic capacity of PCa. Full article

(This article belongs to the Special Issue Targeting Cancer Metastasis (Volume II))

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16 pages, 2855 KiB

Open AccessArticle

H3F3A K27M Mutation Promotes the Infiltrative Growth of High-Grade Glioma in Adults by Activating β-Catenin/USP1 Signaling

by Zhiyuan Sun, Yufu Zhu, Xia Feng, Xiaoyun Liu, Kunlin Zhou, Qing Wang, Hengzhu Zhang and Hengliang Shi

Cancers 2022, 14(19), 4836; https://doi.org/10.3390/cancers14194836 - 3 Oct 2022

Cited by 1 | Viewed by 2406

Abstract

H3F3A K27M (H3.3K27M) is a newly identified molecular pathological marker in glioma and is strongly correlated with the malignancy of diffuse intrinsic pontine glioma (DIPG). In recent years, accumulating evidence has revealed that other types of glioma also contain the H3.3K27M mutation. However, [...] Read more.

H3F3A K27M (H3.3K27M) is a newly identified molecular pathological marker in glioma and is strongly correlated with the malignancy of diffuse intrinsic pontine glioma (DIPG). In recent years, accumulating evidence has revealed that other types of glioma also contain the H3.3K27M mutation. However, the role of H3.3K27M in high-grade adult glioma, the most malignant glioma, has not been investigated. In this study, we focused on exploring the expression and function of H3.3K27M in high-grade glioma in adults. We found that H3.3K27M was highly expressed at high levels in some high-grade glioma tissues. Then, we introduced H3.3K27M into H3.3 wild-type glioma cells, U87 cells and LN229 cells. We found that H3.3K27M did not affect the growth of glioma cells in vitro and in vivo; however, the survival of mice with transplanted tumors was significantly reduced. Further investigation revealed that H3.3K27M expression mainly promoted the migration and invasion of glioma cells. Moreover, we confirmed that H3.3K27M overexpression increased the levels of the β-catenin and p-β-catenin (Ser675) proteins, the ubiquitin-specific protease 1 (USP1) mRNA and protein levels, and the enhancer of zeste homolog 2 (EZH2) protein level. In addition, the β-catenin inhibitor XAV-939 significantly attenuated the upregulation of the aforementioned proteins and inhibited the increased migration and invasion caused by the H3.3K27M mutation. Overall, the H3.3K27M mutation in high-grade glioma is a potential biomarker for poor prognosis mainly due to the infiltration of glioma cells that is at least partially mediated by the β-catenin/USP1/EZH2 pathway. Full article

(This article belongs to the Special Issue Targeting Cancer Metastasis (Volume II))

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13 pages, 3616 KiB

Open AccessArticle

SIPA1 Regulates LINC01615 to Promote Metastasis in Triple-Negative Breast Cancer

by Yuan Xiang, Lingyun Feng, Hui Liu, Yuhuan Liu, Jiapeng Li, Li Su and Xinghua Liao

Cancers 2022, 14(19), 4815; https://doi.org/10.3390/cancers14194815 - 1 Oct 2022

Cited by 6 | Viewed by 1863

Abstract

Long non-coding RNAs (lncRNAs) are reported to play an important regulatory effect in carcinogenesis and malignancy. We found by high-throughput sequencing that LINC01615 is upregulated in breast cancer patients and reduces patients’ overall survival. In vivo and in vitro experiments, we clarified that [...] Read more.

Long non-coding RNAs (lncRNAs) are reported to play an important regulatory effect in carcinogenesis and malignancy. We found by high-throughput sequencing that LINC01615 is upregulated in breast cancer patients and reduces patients’ overall survival. In vivo and in vitro experiments, we clarified that overexpression of LINC01615 can promote breast cancer cell metastasis ability. The expression of LINC01615 is regulated by the transcriptional activator SIPA1, thereby promoting carcinogenesis in breast cancer cells. Our research clarified that LINC01615 can act as an oncogenic factor in promoting the development of breast cancer. Full article

(This article belongs to the Special Issue Targeting Cancer Metastasis (Volume II))

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Review

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25 pages, 1454 KiB

Open AccessReview

A Multi-Omics Overview of Colorectal Cancer to Address Mechanisms of Disease, Metastasis, Patient Disparities and Outcomes

by Guang Yang, Xi (Richard) Yu, Daniel J. Weisenberger, Tao Lu and Gangning Liang

Cancers 2023, 15(11), 2934; https://doi.org/10.3390/cancers15112934 - 26 May 2023

Cited by 5 | Viewed by 2791

Abstract

Human colorectal cancer (CRC) is one of the most common malignancies in men and women across the globe, albeit CRC incidence and mortality shows a substantial racial and ethnic disparity, with the highest burden in African American patients. Even with effective screening tools [...] Read more.

Human colorectal cancer (CRC) is one of the most common malignancies in men and women across the globe, albeit CRC incidence and mortality shows a substantial racial and ethnic disparity, with the highest burden in African American patients. Even with effective screening tools such as colonoscopy and diagnostic detection assays, CRC remains a substantial health burden. In addition, primary tumors located in the proximal (right) or distal (left) sides of the colorectum have been shown to be unique tumor types that require unique treatment schema. Distal metastases in the liver and other organ systems are the major causes of mortality in CRC patients. Characterizing genomic, epigenomic, transcriptomic and proteomic (multi-omics) alterations has led to a better understanding of primary tumor biology, resulting in targeted therapeutic advancements. In this regard, molecular-based CRC subgroups have been developed that show correlations with patient outcomes. Molecular characterization of CRC metastases has highlighted similarities and differences between metastases and primary tumors; however, our understanding as to how to improve patient outcomes based on metastasis biology is lagging and remains a major obstacle to improving CRC patient outcomes. In this review, we will summarize the multi-omics features of primary CRC tumors and their metastases across racial and ethnic groups, the differences in proximal and distal tumor biology, molecular-based CRC subgroups, treatment strategies and challenges for improving patient outcomes. Full article

(This article belongs to the Special Issue Targeting Cancer Metastasis (Volume II))

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23 pages, 2473 KiB

Open AccessReview

Inhibitory Potential of Resveratrol in Cancer Metastasis: From Biology to Therapy

by Baohong Song, Wei Wang, Xuemei Tang, Robby Miguel Wen-Jing Goh, Win Lwin Thuya, Paul Chi Lui Ho, Lu Chen and Lingzhi Wang

Cancers 2023, 15(10), 2758; https://doi.org/10.3390/cancers15102758 - 14 May 2023

Cited by 13 | Viewed by 3617

Abstract

Cancer metastasis is a significant challenge in cancer treatment, and most existing drugs are designed to inhibit tumor growth but are often ineffective in treating metastatic cancer, which is the leading cause of cancer-related deaths. Resveratrol, a polyphenol found in grapes, berries, and [...] Read more.

Cancer metastasis is a significant challenge in cancer treatment, and most existing drugs are designed to inhibit tumor growth but are often ineffective in treating metastatic cancer, which is the leading cause of cancer-related deaths. Resveratrol, a polyphenol found in grapes, berries, and peanuts, has shown potential in preclinical studies as an anticancer agent to suppress metastasis. However, despite positive results in preclinical studies, little progress has been made in clinical trials. To develop resveratrol as an effective anticancer agent, it is crucial to understand its cellular processes and signaling pathways in tumor metastasis. This review article evaluates the current state and future development strategies of resveratrol to enhance its potency against cancer metastasis within its therapeutic dose. In addition, we critically evaluate the animal models used in preclinical studies for cancer metastasis and discuss novel techniques to accelerate the translation of resveratrol from bench to bedside. The appropriate selection of animal models is vital in determining whether resveratrol can be further developed as an antimetastatic drug in cancer therapy. Full article

(This article belongs to the Special Issue Targeting Cancer Metastasis (Volume II))

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19 pages, 1941 KiB

Open AccessReview

Theranostic Applications of Glycosaminoglycans in Metastatic Renal Cell Carcinoma

by San Hue Hua, Maximillian Viera, George W. Yip and Boon Huat Bay

Cancers 2023, 15(1), 266; https://doi.org/10.3390/cancers15010266 - 30 Dec 2022

Cited by 7 | Viewed by 3012

Abstract

Renal cell carcinoma (RCC) makes up the majority of kidney cancers, with a poor prognosis for metastatic RCC (mRCC). Challenges faced in the management of mRCC, include a lack of reliable prognostic markers and biomarkers for precise monitoring of disease treatment, together with [...] Read more.

Renal cell carcinoma (RCC) makes up the majority of kidney cancers, with a poor prognosis for metastatic RCC (mRCC). Challenges faced in the management of mRCC, include a lack of reliable prognostic markers and biomarkers for precise monitoring of disease treatment, together with the potential risk of toxicity associated with more recent therapeutic options. Glycosaminoglycans (GAGs) are a class of carbohydrates that can be categorized into four main subclasses, viz., chondroitin sulfate, hyaluronic acid, heparan sulfate and keratan sulfate. GAGs are known to be closely associated with cancer progression and modulation of metastasis by modification of the tumor microenvironment. Alterations of expression, composition and spatiotemporal distribution of GAGs in the extracellular matrix (ECM), dysregulate ECM functions and drive cancer invasion. In this review, we focus on the clinical utility of GAGs as biomarkers for mRCC (which is important for risk stratification and strategizing effective treatment protocols), as well as potential therapeutic targets that could benefit patients afflicted with advanced RCC. Besides GAG-targeted therapies that holds promise in mRCC, other potential strategies include utilizing GAGs as drug carriers and their mimetics to counter cancer progression, and enhance immunotherapy through binding and transducing signals for immune mediators. Full article

(This article belongs to the Special Issue Targeting Cancer Metastasis (Volume II))

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25 pages, 1188 KiB

Open AccessReview

Non-Coding RNAs of Extracellular Vesicles: Key Players in Organ-Specific Metastasis and Clinical Implications

by Qian Jiang, Xiao-Ping Tan, Cai-Hua Zhang, Zhi-Yuan Li, Du Li, Yan Xu, Yu Xuan Liu, Lingzhi Wang and Zhaowu Ma

Cancers 2022, 14(22), 5693; https://doi.org/10.3390/cancers14225693 - 19 Nov 2022

Cited by 5 | Viewed by 2436

Abstract

Extracellular vesicles (EVs) are heterogeneous membrane-encapsulated vesicles released by most cells. They act as multifunctional regulators of intercellular communication by delivering bioactive molecules, including non-coding RNAs (ncRNAs). Metastasis is a major cause of cancer-related death. Most cancer cells disseminate and colonize a specific [...] Read more.

Extracellular vesicles (EVs) are heterogeneous membrane-encapsulated vesicles released by most cells. They act as multifunctional regulators of intercellular communication by delivering bioactive molecules, including non-coding RNAs (ncRNAs). Metastasis is a major cause of cancer-related death. Most cancer cells disseminate and colonize a specific target organ via EVs, a process known as “organ-specific metastasis”. Mounting evidence has shown that EVs are enriched with ncRNAs, and various EV-ncRNAs derived from tumor cells influence organ-specific metastasis via different mechanisms. Due to the tissue-specific expression of EV-ncRNAs, they could be used as potential biomarkers and therapeutic targets for the treatment of tumor metastasis in various types of cancer. In this review, we have discussed the underlying mechanisms of EV-delivered ncRNAs in the most common organ-specific metastases of liver, bone, lung, brain, and lymph nodes. Moreover, we summarize the potential clinical applications of EV-ncRNAs in organ-specific metastasis to fill the gap between benches and bedsides. Full article

(This article belongs to the Special Issue Targeting Cancer Metastasis (Volume II))

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