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From Progression to Metastasis of Solid Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (20 May 2022) | Viewed by 53356

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Special Issue Editors

Prof. Dr. Eldad Zacksenhaus

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Guest Editor

Toronto General Research Institute, University Health Network, 67 College Street, Toronto, ON M5G 2M1, Canada
Interests: breast cancer; tumor suppressors; retinoblastoma gene and protein; mouse models; cancer stem cells

Prof. Sean Egan

E-Mail Website
Guest Editor

1. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
2. Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada
Interests: Breast cancer; cancer invasion; Notch, signal transduction, genetic screens, chromosomal engineering; mouse models

Special Issue Information

Dear colleagues,

The disruption of normal physiology by the distal growth of cancer cells in bones, brain, liver, lung, and other organs is a major cause of morbidity from many solid cancers. Cancer cells spread to distal sites through the tumor invasion front or through the metastasis of disseminating tumor cells (DTCs) that split off from the primary lesion and circulate via the hematogenous system. By understanding the steps involved in tumor invasion and metastasis, novel targets for intervention may be identified. Indeed, extravasation and dissemination of DTCs through hematogenous routes to metastatic niches, colonization, and the formation of macro-metastases involve processes that are radically different from those that drive primary tumors.

Tumor growth is driven by oncogenic and epigenetic alterations that select for aggressive clones through Darwinian competition in conjunction with the surrounding ecosystem, particularly the tumor immune microenvironment (TIME). While some clones dominate the primary lesion, others may sprout DTCs, and should be preferentially targeted for therapy. The biology of DTCs, their metabolism, dormancy, plasticity (epithelial–mesenchymal and mesenchymal–epithelial transitions as well as stemness) and competence to re-enter the cell cycle at distal sites are critical for metastasis. They also impact drug resistance and relapse. The advent of single-cell sequencing technologies, high-resolution immune-landscape analysis and metabolic profiling of primary tumor, DTCs, and metastatic biopsies, in combination with functional genomic editing of immune-competent mouse models, is helping to create new paradigms in understanding cancer progression to metastasis, uncovering new vulnerabilities and establishing rational frameworks for novel therapeutic intervention.

This special issue of Cancers invites original studies that expose novel mechanisms of solid cancer progression and metastasis, with an eye on novel therapeutic targeting. In particular, we welcome articles that analyze oncogenic processes that promote tumor invasion, dissemination, tumor–TIME interactions, DTCs, and the response to therapy in the primary, invasive front, hematogenous, and metastatic niches using clinical data and preclinical animal models.

Prof. Dr. Eldad Zacksenhaus
Prof. Sean Egan
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

solid cancer
invasion
progression
metastasis
disseminating tumor cells
tumor immune microenvironment
stemness
EMT
MET
single-cell sequencing technologies
high-resolution immune landscape
metabolic profiling

Published Papers (14 papers)

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Editorial

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7 pages, 443 KiB

Open AccessEditorial

Thinking (Metastasis) outside the (Primary Tumor) Box

by Zhe Jiang, Young-Jun Ju, Amjad Ali, Philip E. D. Chung, Dong-Yu Wang, Jeff C. Liu, Huiqin Li, Ioulia Vorobieva, Ethel Mwewa, Ronak Ghanbari-Azarnier, Mariusz Shrestha, Yaacov Ben-David and Eldad Zacksenhaus

Cancers 2023, 15(22), 5315; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15225315 - 07 Nov 2023

Viewed by 918

Abstract

The metastasis of tumor cells into vital organs is a major cause of death from diverse types of malignancies [...] Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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8 pages, 544 KiB

Open AccessEditorial

Progression to Metastasis of Solid Cancer

by Eldad Zacksenhaus and Sean E. Egan

Cancers 2021, 13(4), 717; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040717 - 10 Feb 2021

Cited by 8 | Viewed by 2006

Abstract

Metastatic dissemination of cancer cells, their colonization at distal sites, and ultimate disruption of tissue physiology are the root causes of most deaths from solid cancers, particularly in tumor types where the primary lesion can be easily dissected and discarded [...] Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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Research

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19 pages, 3688 KiB

Open AccessArticle

Yoda1 Enhanced Low-Magnitude High-Frequency Vibration on Osteocytes in Regulation of MDA-MB-231 Breast Cancer Cell Migration

by Chun-Yu Lin, Xin Song, Yaji Ke, Arjun Raha, Yuning Wu, Murtaza Wasi, Liyun Wang, Fei Geng and Lidan You

Cancers 2022, 14(14), 3395; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143395 - 13 Jul 2022

Cited by 12 | Viewed by 2688

Abstract

Low-magnitude (≤1 g) high-frequency (≥30 Hz) (LMHF) vibration has been shown to enhance bone mineral density. However, its regulation in breast cancer bone metastasis remains controversial for breast cancer patients and elder populations. Yoda1, an activator of the mechanosensitive Piezo1 channel, could potentially intensify the effect of LMHF vibration by enhancing the mechanoresponse of osteocytes, the major mechanosensory bone cells with high expression of Piezo1. In this study, we treated osteocytes with mono- (Yoda1 only or vibration only) or combined treatment (Yoda1 and LMHF vibration) and examined the further regulation of osteoclasts and breast cancer cells through the conditioned medium. Moreover, we studied the effects of combined treatment on breast cancer cells in regulation of osteocytes. Combined treatment on osteocytes showed beneficial effects, including increasing the nuclear translocation of Yes-associated protein (YAP) in osteocytes (488.0%, p < 0.0001), suppressing osteoclastogenesis (34.3%, p = 0.004), and further reducing migration of MDA-MB-231 (15.1%, p = 0.02) but not Py8119 breast cancer cells (4.2%, p = 0.66). Finally, MDA-MB-231 breast cancer cells subjected to the combined treatment decreased the percentage of apoptotic osteocytes (34.5%, p = 0.04) but did not affect the intracellular calcium influx. This study showed the potential of stimulating Piezo1 in enhancing the mechanoresponse of osteocytes to LMHF vibration and further suppressing breast cancer migration via osteoclasts. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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26 pages, 6441 KiB

Open AccessArticle

Impact of Secretion-Active Osteoblast-Specific Factor 2 in Promoting Progression and Metastasis of Head and Neck Cancer

by Désirée Gül, Andrea Schweitzer, Aya Khamis, Shirley K. Knauer, Guo-Bin Ding, Laura Freudelsperger, Ioannis Karampinis, Sebastian Strieth, Jan Hagemann and Roland H. Stauber

Cancers 2022, 14(9), 2337; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092337 - 09 May 2022

Cited by 4 | Viewed by 2080

Abstract

Treatment success of head and neck cancer (HNC) is still hampered by tumor relapse due to metastases. Our study aimed to identify biomarkers by exploiting transcriptomics profiles of patient-matched metastases, primary tumors, and normal tissue mucosa as well as the TCGA HNC cohort data sets. Analyses identified osteoblast-specific factor 2 (OSF-2) as significantly overexpressed in lymph node metastases and primary tumors compared to normal tissue. High OSF-2 levels correlate with metastatic disease and reduced overall survival of predominantly HPV-negative HNC patients. No significant correlation was observed with tumor localization or therapy response. These findings were supported by the fact that OSF-2 expression was not elevated in cisplatin-resistant HNC cell lines. OSF-2 was strongly expressed in tumor-associated fibroblasts, suggesting a tumor microenvironment-promoting function. Molecular cloning and expression studies of OSF-2 variants from patients identified an evolutionary conserved bona fide protein secretion signal (¹MIPFLPMFSLLLLLIVNPINA²¹). OSF-2 enhanced cell migration and cellular survival under stress conditions, which could be mimicked by the extracellular administration of recombinant protein. Here, OSF-2 executes its functions via ß1 integrin, resulting in the phosphorylation of PI3K and activation of the Akt/PKB signaling pathway. Collectively, we suggest OSF-2 as a potential prognostic biomarker and drug target, promoting metastases by supporting the tumor microenvironment and lymph node metastases survival rather than by enhancing primary tumor proliferation or therapy resistance. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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22 pages, 1520 KiB

Open AccessArticle

The Role of Treatment Sequencing with Immune-Checkpoint Inhibitors and BRAF/MEK Inhibitors for Response and Survival of Patients with BRAFV600-Mutant Metastatic Melanoma—A Retrospective, Real-World Cohort Study

by Maximilian Haist, Henner Stege, Ronja Ebner, Maria Isabel Fleischer, Carmen Loquai and Stephan Grabbe

Cancers 2022, 14(9), 2082; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092082 - 21 Apr 2022

Cited by 9 | Viewed by 1709

Abstract

The advent of immune-checkpoint inhibitors (CPI) and BRAF/MEK-directed targeted therapy (TT) has improved the treatment landscape of patients with BRAFV600-mutant metastatic melanoma. While TT allows for rapid disease control, the development of secondary TT resistance limits the duration of responses. Responses to CPI have a slower onset but can be durable in a subset of patients. To date, little prospective data is available for the optimal sequencing of these agents in melanoma patients. In this retrospective, single-center, real-world analysis, we identified 135 patients with BRAF-mutated, metastatic melanoma who received consecutive treatment with TT followed by CPI, or vice versa, as first and second-line therapy, respectively. We collected data on clinical-pathological factors, treatment duration, best overall response, progression-free survival and overall survival (OS). Our data revealed that front-line treatment with CPI, followed by TT, showed a non-significant trend towards better OS compared to front-line TT (median OS: 35.0 vs. 18.0 months, p = 0.070). This association was confirmed in a subgroup of patients without systemic pre-treatments (median OS: 41.0 vs. 14.0 months, p = 0.02). Further, we observed significantly better objective response rates to second-line treatments for patients receiving front-line CPI (18.4 vs. 37.8%, p = 0.024). Last, our results indicated that rapid disease progression was less common in patients treated with front-line CPI (27.6% vs. 16.2%) and that subsequent treatment with TT resulted in favorable survival outcomes. Our real-world data indicate that sequential treatment with front-line CPI is associated with favorable tumor control and overall survival in a subgroup of previously untreated BRAF-mutant metastatic melanoma patients. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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18 pages, 5498 KiB

Open AccessArticle

Slow-Cycling Cells in Glioblastoma: A Specific Population in the Cellular Mosaic of Cancer Stem Cells

by Changlin Yang, Guimei Tian, Mariana Dajac, Andria Doty, Shu Wang, Ji-Hyun Lee, Maryam Rahman, Jianping Huang, Brent A. Reynolds, Matthew R. Sarkisian, Duane Mitchell and Loic P. Deleyrolle

Cancers 2022, 14(5), 1126; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051126 - 23 Feb 2022

Cited by 8 | Viewed by 3231

Abstract

Glioblastoma (GBM) exhibits populations of cells that drive tumorigenesis, treatment resistance, and disease progression. Cells with such properties have been described to express specific surface and intracellular markers or exhibit specific functional states, including being slow-cycling or quiescent with the ability to generate proliferative progenies. In GBM, each of these cellular fractions was shown to harbor cardinal features of cancer stem cells (CSCs). In this study, we focus on the comparison of these cells and present evidence of great phenotypic and functional heterogeneity in brain cancer cell populations with stemness properties, especially between slow-cycling cells (SCCs) and cells phenotypically defined based on the expression of markers commonly used to enrich for CSCs. Here, we present an integrative analysis of the heterogeneity present in GBM cancer stem cell populations using a combination of approaches including flow cytometry, bulk RNA sequencing, and single cell transcriptomics completed with functional assays. We demonstrated that SCCs exhibit a diverse range of expression levels of canonical CSC markers. Importantly, the property of being slow-cycling and the expression of these markers were not mutually inclusive. We interrogated a single-cell RNA sequencing dataset and defined a group of cells as SCCs based on the highest score of a specific metabolic signature. Multiple CSC groups were determined based on the highest expression level of CD133, SOX2, PTPRZ1, ITGB8, or CD44. Each group, composed of 22 cells, showed limited cellular overlap, with SCCs representing a unique population with none of the 22 cells being included in the other groups. We also found transcriptomic distinctions between populations, which correlated with clinicopathological features of GBM. Patients with strong SCC signature score were associated with shorter survival and clustered within the mesenchymal molecular subtype. Cellular diversity amongst these populations was also demonstrated functionally, as illustrated by the heterogenous response to the chemotherapeutic agent temozolomide. In conclusion, our study supports the cancer stem cell mosaicism model, with slow-cycling cells representing critical elements harboring key features of disseminating cells. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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14 pages, 3375 KiB

Open AccessArticle

Adipsin-Dependent Secretion of Hepatocyte Growth Factor Regulates the Adipocyte-Cancer Stem Cell Interaction

by Masahiro Mizuno, Behnoush Khaledian, Masao Maeda, Takanori Hayashi, Seiya Mizuno, Eiji Munetsuna, Takashi Watanabe, Seishi Kono, Seiji Okada, Motoshi Suzuki, Shintaro Takao, Hironobu Minami, Naoya Asai, Fumihiro Sugiyama, Satoru Takahashi and Yohei Shimono

Cancers 2021, 13(16), 4238; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164238 - 23 Aug 2021

Cited by 8 | Viewed by 3553

Abstract

Adipose tissue is a component of the tumor microenvironment and is involved in tumor progression. We have previously shown that adipokine adipsin (CFD) functions as an enhancer of tumor proliferation and cancer stem cell (CSC) properties in breast cancers. We established the Cfd-knockout (KO) mice and the mammary adipose tissue-derived stem cells (mADSCs) from them. Cfd-KO in mADSCs significantly reduced their ability to enhance tumorsphere formation of breast cancer patient-derived xenograft (PDX) cells, which was restored by the addition of Cfd in the culture medium. Hepatocyte growth factor (HGF) was expressed and secreted from mADSCs in a Cfd-dependent manner. HGF rescued the reduced ability of Cfd-KO mADSCs to promote tumorsphere formation in vitro and tumor formation in vivo by breast cancer PDX cells. These results suggest that HGF is a downstream effector of Cfd in mADSCs that enhances the CSC properties in breast cancers. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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Review

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23 pages, 707 KiB

Open AccessReview

The Hepatic Pre-Metastatic Niche

by Benjamin Ormseth, Amblessed Onuma, Hongji Zhang and Allan Tsung

Cancers 2022, 14(15), 3731; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14153731 - 31 Jul 2022

Cited by 3 | Viewed by 2921

Abstract

Primary tumors can communicate with the liver to establish a microenvironment that favors metastatic colonization prior to dissemination, forming what is termed the “pre-metastatic niche” (PMN). Through diverse signaling mechanisms, distant malignancies can both influence hepatic cells directly as well as recruit immune cells into the PMN. The result is a set of changes within the hepatic tissue that increase susceptibility of tumor cell invasion and outgrowth upon dissemination. Thus, the PMN offers a novel step in the traditional metastatic cascade that could offer opportunities for clinical intervention. The involved signaling molecules also offer promise as biomarkers. Ultimately, while the existence of the hepatic PMN is well-established, continued research effort and use of innovative models are required to reach a functional knowledge of PMN mechanisms that can be further targeted. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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15 pages, 1412 KiB

Open AccessEditor’s ChoiceReview

AXL Receptor Tyrosine Kinase as a Promising Therapeutic Target Directing Multiple Aspects of Cancer Progression and Metastasis

by Marie-Anne Goyette and Jean-François Côté

Cancers 2022, 14(3), 466; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030466 - 18 Jan 2022

Cited by 20 | Viewed by 4703

Abstract

The receptor tyrosine kinase AXL is emerging as a key player in tumor progression and metastasis and its expression correlates with poor survival in a plethora of cancers. While studies have shown the benefits of AXL inhibition for the treatment of metastatic cancers, additional roles for AXL in cancer progression are still being explored. This review discusses recent advances in understanding AXL’s functions in different tumor compartments including cancer, vascular, and immune cells. AXL is required at multiple steps of the metastatic cascade where its activation in cancer cells leads to EMT, invasion, survival, proliferation and therapy resistance. AXL activation in cancer cells and various stromal cells also results in tumor microenvironment deregulation, leading to modulation of angiogenesis, fibrosis, immune response and hypoxia. A better understanding of AXL’s role in these processes could lead to new therapeutic approaches that would benefit patients suffering from metastatic diseases. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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15 pages, 1446 KiB

Open AccessReview

BRCA1 and Metastasis: Outcome of Defective DNA Repair

by Rehna Krishnan, Parasvi S. Patel and Razqallah Hakem

Cancers 2022, 14(1), 108; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010108 - 27 Dec 2021

Cited by 12 | Viewed by 6947

Abstract

Heritable mutations in BRCA1 and BRCA2 genes are a major risk factor for breast and ovarian cancer. Inherited mutations in BRCA1 increase the risk of developing breast cancers by up to 72% and ovarian cancers by up to 69%, when compared to individuals with wild-type BRCA1. BRCA1 and BRCA2 (BRCA1/2) are both important for homologous recombination-mediated DNA repair. The link between BRCA1/2 mutations and high susceptibility to breast cancer is well established. However, the potential impact of BRCA1 mutation on the individual cell populations within a tumor microenvironment, and its relation to increased aggressiveness of cancer is not well understood. The objective of this review is to provide significant insights into the mechanisms by which BRCA1 mutations contribute to the metastatic and aggressive nature of the tumor cells. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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17 pages, 337 KiB

Open AccessReview

Clinical Biomarkers for Early Identification of Patients with Intracranial Metastatic Disease

by Karolina Gaebe, Alyssa Y. Li and Sunit Das

Cancers 2021, 13(23), 5973; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13235973 - 27 Nov 2021

Cited by 4 | Viewed by 1719

Abstract

Nearly 30% of patients with cancer will develop intracranial metastatic disease (IMD), and more than half of these patients will die within a few months following their diagnosis. In light of the profound effect of IMD on survival and quality of life, there is significant interest in identifying biomarkers that could facilitate the early detection of IMD or identify patients with cancer who are at high IMD risk. In this review, we will highlight early efforts to identify biomarkers of IMD and consider avenues for future investigation. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

22 pages, 1366 KiB

Open AccessReview

The Breast Tumor Microenvironment: A Key Player in Metastatic Spread

by Lucas E. L. Terceiro, Chidalu A. Edechi, Nnamdi M. Ikeogu, Barbara E. Nickel, Sabine Hombach-Klonisch, Tanveer Sharif, Etienne Leygue and Yvonne Myal

Cancers 2021, 13(19), 4798; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194798 - 25 Sep 2021

Cited by 25 | Viewed by 8448

Abstract

The tumor microenvironment plays a pivotal role in the tumorigenesis, progression, and metastatic spread of many cancers including breast. There is now increasing evidence to support the observations that a bidirectional interplay between breast cancer cells and stromal cells exists within the tumor and the tumor microenvironment both at the primary tumor site and at the metastatic site. This interaction occurs through direct cell to cell contact, or by the release of autocrine or paracrine factors which can activate pro-tumor signaling pathways and modulate tumor behavior. In this review, we will highlight recent advances in our current knowledge about the multiple interactions between breast cancer cells and neighboring cells (fibroblasts, endothelial cells, adipocytes, innate and adaptive immune cells) in the tumor microenvironment that coordinate to regulate metastasis. We also highlight the role of exosomes and circulating tumor cells in facilitating breast cancer metastasis. We discuss some key markers associated with stromal cells in the breast tumor environment and their potential to predict patient survival and guide treatment. Finally, we will provide some brief perspectives on how current technologies may lead to the development of more effective therapies for the clinical management of breast cancer patients. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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16 pages, 1475 KiB

Open AccessReview

The Underlying Biology and Therapeutic Vulnerabilities of Leptomeningeal Metastases in Adult Solid Cancers

by Matthew Dankner, Stephanie Lam, Theresa Degenhard, Livia Garzia, Marie-Christine Guiot, Kevin Petrecca and Peter M. Siegel

Cancers 2021, 13(4), 732; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040732 - 10 Feb 2021

Cited by 16 | Viewed by 7650

Abstract

Metastasis to the central nervous system occurs in approximately 20% of patients with advanced solid cancers such as lung cancer, breast cancer, and melanoma. While central nervous system metastases most commonly form in the brain parenchyma, metastatic cancer cells may also reside in the subarachnoid space surrounding the brain and spinal cord to form tumors called leptomeningeal metastases. Leptomeningeal metastasis involves cancer cells that reach the subarachnoid space and proliferate in the cerebrospinal fluid compartment within the leptomeninges, a sequela associated with a myriad of symptoms and poor prognosis. Cancer cells exposed to cerebrospinal fluid in the leptomeninges must contend with a unique microenvironment from those that establish within the brain or other organs. Leptomeningeal lesions provide a formidable clinical challenge due to their often-diffuse infiltration within the subarachnoid space. The molecular mechanisms that promote the establishment of leptomeningeal metastases have begun to be elucidated, demonstrating that it is a biological entity distinct from parenchymal brain metastases and is associated with specific molecular drivers. In this review, we outline the current state of knowledge pertaining to the diagnosis, treatment, and molecular underpinnings of leptomeningeal metastasis. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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Other

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17 pages, 1747 KiB

Open AccessPerspective

New Perspectives on the Role of Integrin-Linked Kinase (ILK) Signaling in Cancer Metastasis

by Paul C. McDonald and Shoukat Dedhar

Cancers 2022, 14(13), 3209; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133209 - 30 Jun 2022

Cited by 10 | Viewed by 2466

Abstract

Cancer metastasis is a major barrier to the long-term survival of cancer patients. In cancer cells, integrin engagement downstream of cell-extracellular matrix (ECM) interactions results in the recruitment of cytoskeletal and signaling molecules to form multi-protein complexes to promote processes critical for metastasis. One of the major functional components of these complexes is Integrin Linked Kinase (ILK). Here, we discuss recent advances in our understanding of the importance of ILK as a signaling effector in processes linked to tumor progression and metastasis. New mechanistic insights as to the role of ILK in cellular plasticity, epithelial mesenchymal transition (EMT), migration, and invasion, including the impact of ILK on the formation of invadopodia, filopodia-like protrusions (FLPs), and Neutrophil Extracellular Trap (NET)-induced motility are highlighted. Recent findings detailing the contribution of ILK to therapeutic resistance and the importance of ILK as a potentially therapeutically tractable vulnerability in both solid tumors and hematologic malignancies are discussed. Indeed, pharmacologic inhibition of ILK activity using specific small molecule inhibitors is effective in curtailing the contribution of ILK to these processes, potentially offering a novel therapeutic avenue for inhibiting critical steps in the metastatic cascade leading to reduced drug resistance and increased therapeutic efficacy. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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