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Tumor Microenvironment and Actin Cytoskeleton in Cancer Cell Metastasis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 30051

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Special Issue Editors

Prof. Dr. Triantafyllos Stylianopoulos

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Guest Editor

Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 2109, Cyprus
Interests: combining computational approaches with state-of-the-art experimental techniques to explore the mechanopathology of cancer and overcome the barriers to the effective delivery of drugs to solid tumors; emphasis is placed on the application of principles from engineering and biology in order to investigate the mechanisms with which physical forces are related to tumor growth, progression, and treatment

Dr. Vasiliki Gkretsi

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Co-Guest Editor

Cancer Metastasis and Adhesion Laboratory, Basic and Translational Cancer Research Center (BTCRC), European University Cyprus, 2404 Nicosia, Cyprus
Interests: actin cytoskeleton; focal adhesions; extracellular matrix; cancer cell metastasis
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Special Issue Information

Dear Colleagues,

Most cancer-related deaths are not due to the primary tumor but, rather, due to the dissemination of cancer cells to other sites of the body through a process known as metastasis. For metastasis to take place, cells need to properly regulate their adhesion both to the extracellular matrix and the neighboring cells, as well as to coordinate actin cytoskeleton dynamics, to be able to finally detach from the original tumor mass, migrate, and invade through adjacent normal tissue to eventually reach another environment and establish a new metastatic colony there. Despite active research efforts in the field, there are still questions to be answered in order to better understand the cellular and molecular mechanisms governing cancer cell metastasis and the involvement of actin-related proteins in the process.

This Special Issue of IJMS will cover a variety of topics with regard to the involvement of tumor microenvironment and actin cytoskeleton in cancer cell metastasis, such as the role of integrin, extracellular matrix-related adhesion proteins, and actin cytoskeleton in cancer cell migration; in vitro and in vivo invasion; the role of tumor microenvironment components in metastasis; the role of actin-binding proteins; the involvement of biomechanics, latest methods, and advanced technologies in monitoring cancer cell metastasis and actin-structures in vitro; and developments with respect to actin-targeting drugs.

Prof. Triantafyllos Stylianopoulos
Dr. Vasiliki Gkretsi
Guest Editors

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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.

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Published Papers (7 papers)

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Research

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16 pages, 1950 KiB

Open AccessArticle

MMP1 and MMP11 Expression in Peripheral Blood Mononuclear Cells upon Their Interaction with Breast Cancer Cells and Fibroblasts

by Noemi Eiro, Sandra Cid, Nuria Aguado, María Fraile, Nagore de Pablo, Berta Fernández, Francisco Domínguez, Luis O. González and Francisco J. Vizoso

Int. J. Mol. Sci. 2021, 22(1), 371; https://doi.org/10.3390/ijms22010371 - 31 Dec 2020

Cited by 12 | Viewed by 3570

Abstract

Tumor-infiltrating immune cells phenotype is associated with tumor progression. However, little is known about the phenotype of the peripheral blood mononuclear cells (PBMC) from breast cancer patients. We investigated MMP1 and MMP11 expression in PBMC from breast cancer patients and we analyzed gene expression changes upon their interaction with cancer cells and cancer-associated fibroblasts (CAF). We measured the impact of PBMC on proinflammatory gene expression in breast cancer cells, normal fibroblast (NF), and CAF and the impact on proliferation and invasiveness capacity of breast cancer cells. Gene expression of MMP1 and MMP11 in PBMC from breast cancer patients (n = 54) and control (n = 28); expression of IL1A, IL6, IL17, IFNβ, and NFĸB in breast cancer cell lines (MCF-7 and MDA-MB-231); and, additionally, IL10 and MMP11 in CAF and NF were analyzed by qRT-PCR before and after co-culture. Our results show the existence of a subpopulation of breast cancer patients (25.9%) with very high levels of MMP11 gene expression in PBMC. Also, gene expression of MMP1 and MMP11 increases in PBMC after co-culture with breast cancer cell lines, NF or CAF. PBMC from healthy or breast cancer patients induce an increased proliferation rate on MCF-7 and an increased invasiveness capacity of MDA-MB-231. Finally, we show a differential expression profile of inflammatory genes in NF and CAF when co-cultured with control or breast cancer PBMC. We have observed that MMPs’ expression in PBMC is regulated by the microenvironment, while the expression of inflammatory genes in NF or CAF is differentially regulated by PBMC. These findings confirm the importance of the crosstalk between stromal cells and suggest that PBMC would play a role in promoting aggressive tumor behavior. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Actin Cytoskeleton in Cancer Cell Metastasis)

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20 pages, 42268 KiB

Open AccessArticle

Depleting RhoA/Stress Fiber-Organized Fibronectin Matrices on Tumor Cells Non-Autonomously Aggravates Fibroblast-Driven Tumor Cell Growth

by Li-Tzu Huang, Chen-Lung Tsai, Shin-Huei Huang, Ming-Min Chang, Wen-Tsan Chang, Li-Hsin Cheng and Hung-Chi Cheng

Int. J. Mol. Sci. 2020, 21(21), 8272; https://doi.org/10.3390/ijms21218272 - 4 Nov 2020

Cited by 2 | Viewed by 3418

Abstract

Fibronectin (FN) expressed by tumor cells has been known to be tumor suppressive but the pericellular FN (periFN) assembled on circulating tumor cells appears to evidently promote distant metastasis. Whereas the regulation of periFN assembly in suspended cells has currently been under investigation, how it is regulated in adherent tumor cells and the role of periFN in primary tumor growth remain elusive. Techniques of RNAi, plasmid transfections, immunoblotting, fluorescence/immunohistochemistry staining, cell proliferation assays, and primary tumor growth in C57BL6 mice and Fischer 344 rats were employed in this study. We found that endogenously synthesized FN in adherent tumor cells was required for periFN assembly which was aligned by RhoA-organized actin stress fiber (SF). Depleting periFN on adherent tumor cells congruently promoted in vivo tumor growth but surprisingly did not autonomously impact on in vitro tumor cell proliferation and apoptosis, suggestive of a non-autonomous role of periFN in in vivo tumor growth. We showed that the proliferative ability of shFN-expressing tumor cells was higher than shScramble cells did in the presence of fibroblasts. Altogether, these results suggested that depriving RhoA/SF-regulated periFN matrices non-autonomously promotes fibroblast-mediated tumor cell growth. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Actin Cytoskeleton in Cancer Cell Metastasis)

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21 pages, 1726 KiB

Open AccessArticle

MicroRNA-Dependent Targeting of RSU1 and the IPP Adhesion Complex Regulates the PTEN/PI3K/AKT Signaling Pathway in Breast Cancer Cell Lines

by Yong-Chul Kim and Mary L. Cutler

Int. J. Mol. Sci. 2020, 21(15), 5458; https://doi.org/10.3390/ijms21155458 - 30 Jul 2020

Cited by 2 | Viewed by 3490

Abstract

(1) Background: The microRNA (miR)-directed control of gene expression is correlated with numerous physiological processes as well as the pathological features of tumors. The focus of this study is on the role of miRs in the regulation of RSU1 and proteins in the IPP (integrin linked kinase, PINCH and parvin) complex. Because the IPP adaptor proteins link β integrins to actin cytoskeleton, and the RSU1 signaling protein connects the complex to the activation of cJun, ATF2 and the transcription of PTEN, their reduction by miRs has the potential to alter both adhesion and survival signaling. (2) Methods: Multiple database analyses were used to identify miRs that target RSU1 and PINCH1. miR transfection validated the effects of miRs on RSU1, PINCH1 and downstream targets in breast cancer cell lines. (3) Results: The miRs targeting RSU1 mRNA include miR-182-5p, -409-3p, -130a-3p, -221-3p, -744-5p and -106b-5p. Data show that miR-182-5p and -409-3p reduce RSU1, PINCH1 and inhibit the ATF2 activation of PTEN expression. miR-221-3p and miR-130a-3p target RSU1 and PINCH1 and, conversely, RSU1 depletion increases miR-221-3p and miR-130a-3p. (4) Conclusions: miRs targeting RSU1 and PINCH1 in mammary epithelial or luminal breast cancer cell lines reduced RSU1 signaling to p38 MAP kinase and ATF2, inhibiting the expression of PTEN. miR-221-3p, known to target PTEN and cell cycle regulators, also targets RSU1 and PINCH1 in luminal breast cancer cell lines. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Actin Cytoskeleton in Cancer Cell Metastasis)

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17 pages, 4029 KiB

Open AccessArticle

Quantitative Phosphoproteomics Reveals Cell Alignment and Mitochondrial Length Change under Cyclic Stretching in Lung Cells

by Wei-Hsuan Wang, Chia-Lang Hsu, Hsuan-Cheng Huang and Hsueh-Fen Juan

Int. J. Mol. Sci. 2020, 21(11), 4074; https://doi.org/10.3390/ijms21114074 - 7 Jun 2020

Cited by 4 | Viewed by 3960

Abstract

Lung cancer is a leading cause of death. Most previous studies have been based on traditional cell-culturing methods. However, lung cells are periodically subjected to mechanical forces during breathing. Understanding the mechanisms underlying the cyclic stretching induced in lung cells may be important for lung cancer therapy. Here, we applied cyclic stretching to stimulate the continual contraction that is present under physiological conditions in lung cells. We first uncovered the stretching-induced phosphoproteome in lung cancer cell line A549 and fibroblast cell line IMR-90. We identified 2048 and 2604 phosphosites corresponding to 837 and 1008 phosphoproteins in A549 and IMR-90, respectively. Furthermore, we combined our phosphoproteomics and public gene expression data to identify the biological functions in response to cyclic stretching. Interestingly, cytoskeletal and mitochondrial reorganization were enriched. We further used cell imaging analysis to validate the profiling results and found that this physical force changed cell alignment and mitochondrial length. This study not only reveals the molecular mechanism of cyclic stretching but also provides evidence that cell stretching causes cellular rearrangement and mitochondrial length change. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Actin Cytoskeleton in Cancer Cell Metastasis)

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Review

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15 pages, 1102 KiB

Open AccessReview

Tumor-Associated Macrophages and Inflammatory Microenvironment in Gastric Cancer: Novel Translational Implications

by Karim Rihawi, Angela Dalia Ricci, Alessandro Rizzo, Stefano Brocchi, Giovanni Marasco, Luigi Vincenzo Pastore, Fabiola Lorena Rojas Llimpe, Rita Golfieri and Matteo Renzulli

Int. J. Mol. Sci. 2021, 22(8), 3805; https://doi.org/10.3390/ijms22083805 - 7 Apr 2021

Cited by 85 | Viewed by 4683

Abstract

Gastric cancer (GC) represents the fifth most frequently diagnosed cancer worldwide, with a poor prognosis in patients with advanced disease despite many improvements in systemic treatments in the last decade. In fact, GC has shown resistance to several treatment options, and thus, notable efforts have been focused on the research and identification of novel therapeutic targets in this setting. The tumor microenvironment (TME) has emerged as a potential therapeutic target in several malignancies including GC, due to its pivotal role in cancer progression and drug resistance. Therefore, several agents and therapeutic strategies targeting the TME are currently under assessment in both preclinical and clinical studies. The present study provides an overview of available evidence of the inflammatory TME in GC, highlighting different types of tumor-associated cells and implications for future therapeutic strategies. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Actin Cytoskeleton in Cancer Cell Metastasis)

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13 pages, 980 KiB

Open AccessReview

Ras Suppressor-1 (RSU1) in Cancer Cell Metastasis: A Tale of a Tumor Suppressor

by Maria Louca, Triantafyllos Stylianopoulos and Vasiliki Gkretsi

Int. J. Mol. Sci. 2020, 21(11), 4076; https://doi.org/10.3390/ijms21114076 - 7 Jun 2020

Cited by 7 | Viewed by 3179

Abstract

Cancer is a multifactorial disease responsible for millions of deaths worldwide. It has a strong genetic background, as mutations in oncogenes or tumor suppressor genes contribute to the initiation of cancer development. Integrin signaling as well as the signaling pathway of Ras oncogene, have been long implicated both in carcinogenesis and disease progression. Moreover, they have been involved in the promotion of metastasis, which accounts for the majority of cancer-related deaths. Ras Suppressor-1 (RSU1) was identified as a suppressor of Ras-induced transformation and was shown to localize to cell-extracellular matrix adhesions. Recent findings indicate that its expression is elevated in various cancer types, while its role in regulating metastasis-related cellular processes remains largely unknown. Interestingly, there is no in vivo work in the field to date, and thus, all relevant knowledge stems from in vitro studies. In this review, we summarize recent studies using breast, liver and brain cancer cell lines and highlight the role of RSU1 in regulating cancer cell invasion. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Actin Cytoskeleton in Cancer Cell Metastasis)

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16 pages, 2441 KiB

Open AccessReview

Extracellular BMP Antagonists, Multifaceted Orchestrators in the Tumor and Its Microenvironment

by Sarah Ouahoud, James C.H. Hardwick and Lukas J.A.C. Hawinkels

Int. J. Mol. Sci. 2020, 21(11), 3888; https://doi.org/10.3390/ijms21113888 - 29 May 2020

Cited by 15 | Viewed by 6389

Abstract

The bone morphogenetic proteins (BMPs), a subgroup of the transforming growth factor-β (TGF-β) superfamily, are involved in multiple biological processes such as embryonic development and maintenance of adult tissue homeostasis. The importance of a functional BMP pathway is underlined by various diseases, including cancer, which can arise as a consequence of dysregulated BMP signaling. Mutations in crucial elements of this signaling pathway, such as receptors, have been reported to disrupt BMP signaling. Next to that, aberrant expression of BMP antagonists could also contribute to abrogated signaling. In this review we set out to highlight how BMP antagonists affect not only the cancer cells, but also the other cells present in the microenvironment to influence cancer progression. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Actin Cytoskeleton in Cancer Cell Metastasis)

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