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20 pages, 3455 KiB

Open AccessArticle

Sterculic Acid Alters Adhesion Molecules Expression and Extracellular Matrix Compounds to Regulate Migration of Lung Cancer Cells

by Rafael Peláez, Rodrigo Ochoa, Ana Pariente, Ángela Villanueva-Martínez, Álvaro Pérez-Sala and Ignacio M. Larráyoz

Cancers 2021, 13(17), 4370; https://doi.org/10.3390/cancers13174370 - 29 Aug 2021

Cited by 6 | Viewed by 3059

Abstract

Sterculic acid (SA) is a cyclopropenoid fatty acid isolated from Sterculia foetida seeds. This molecule is a well-known inhibitor of SCD1 enzyme, also known as ∆9-desaturase, which main function is related to lipid metabolism. However, recent studies have demonstrated that it also modifies [...] Read more.

Sterculic acid (SA) is a cyclopropenoid fatty acid isolated from Sterculia foetida seeds. This molecule is a well-known inhibitor of SCD1 enzyme, also known as ∆9-desaturase, which main function is related to lipid metabolism. However, recent studies have demonstrated that it also modifies many other pathways and the underlying gene expression. SCD overexpression, or up-regulated activity, has been associated with tumor aggressiveness and poor prognosis in many cancer types. Scd1 down-regulation, with different inhibitors or molecular strategies, reduces tumor cell survival and cell proliferation, as well as the chemoresistance associated with cancer stem cell presence. However, SA effects over cancer cell migration and extracellular matrix or adhesion molecules have not been described in cancer cells up to now. We used different migration assays and qPCR gene expression analysis to evaluate the effects of SA treatment in cancer cells. The results reveal that SA induces tumoral cell death at high doses, but we also observed that lower SA-treatments induce cell adhesion-migration capacity reduction as a result of modifications in the expression of genes related to integrins and extracellular matrix compounds. Overall, the functional and transcriptomic findings suggest that SA could represent a new inhibitor activity of epithelial to mesenchymal transition. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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17 pages, 3119 KiB

Open AccessArticle

Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor

by Rakshitha Pandulal Miskin, Janine S. A. Warren, Abibatou Ndoye, Lei Wu, John M. Lamar and C. Michael DiPersio

Cancers 2021, 13(3), 480; https://doi.org/10.3390/cancers13030480 - 27 Jan 2021

Cited by 21 | Viewed by 3501

Abstract

In the current study, we demonstrate that integrin α3β1 promotes invasive and metastatic traits of triple-negative breast cancer (TNBC) cells through induction of the transcription factor, Brain-2 (Brn-2). We show that RNAi-mediated suppression of α3β1 in MDA-MB-231 cells caused reduced expression of Brn-2 [...] Read more.

In the current study, we demonstrate that integrin α3β1 promotes invasive and metastatic traits of triple-negative breast cancer (TNBC) cells through induction of the transcription factor, Brain-2 (Brn-2). We show that RNAi-mediated suppression of α3β1 in MDA-MB-231 cells caused reduced expression of Brn-2 mRNA and protein and reduced activity of the BRN2 gene promoter. In addition, RNAi-targeting of Brn-2 in MDA-MB-231 cells decreased invasion in vitro and lung colonization in vivo, and exogenous Brn-2 expression partially restored invasion to cells in which α3β1 was suppressed. α3β1 promoted phosphorylation of Akt in MDA-MB-231 cells, and treatment of these cells with a pharmacological Akt inhibitor (MK-2206) reduced both Brn-2 expression and cell invasion, indicating that α3β1-Akt signaling contributes to Brn-2 induction. Analysis of RNAseq data from patients with invasive breast carcinoma revealed that high BRN2 expression correlates with poor survival. Moreover, high BRN2 expression positively correlates with high ITGA3 expression in basal-like breast cancer, which is consistent with our experimental findings that α3β1 induces Brn-2 in TNBC cells. Together, our study demonstrates a pro-invasive/pro-metastatic role for Brn-2 in breast cancer cells and identifies a role for integrin α3β1 in regulating Brn-2 expression, thereby revealing a novel mechanism of integrin-dependent breast cancer cell invasion. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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16 pages, 3410 KiB

Open AccessArticle

Integrin α3β1 Represses Reelin Expression in Breast Cancer Cells to Promote Invasion

by Abibatou Ndoye, Rakshitha Pandulal Miskin and C. Michael DiPersio

Cancers 2021, 13(2), 344; https://doi.org/10.3390/cancers13020344 - 19 Jan 2021

Cited by 19 | Viewed by 3502

Abstract

Integrin α3β1, a cell adhesion receptor for certain laminins, is known to promote breast tumor growth and invasion. Our previous gene microarray study showed that the RELN gene, which encodes the extracellular glycoprotein Reelin, was upregulated in α3β1-deficient (i.e., α3 knockdown) MDA-MB-231 cells. [...] Read more.

Integrin α3β1, a cell adhesion receptor for certain laminins, is known to promote breast tumor growth and invasion. Our previous gene microarray study showed that the RELN gene, which encodes the extracellular glycoprotein Reelin, was upregulated in α3β1-deficient (i.e., α3 knockdown) MDA-MB-231 cells. In breast cancer, reduced RELN expression is associated with increased invasion and poor prognosis. In this study we demonstrate that α3β1 represses RELN expression to enhance breast cancer cell invasion. RELN mRNA was significantly increased upon RNAi-mediated α3 knockdown in two triple-negative breast cancer cell lines, MDA-MB-231 and SUM159. Modulation of baseline Reelin levels altered invasive potential, where enhanced Reelin expression in MDA-MB-231 cells reduced invasion, while RNAi-mediated suppression of Reelin in SUM159 cells increased invasion. Moreover, treatment of α3β1-expressing MDA-MB-231 cells with culture medium that was conditioned by α3 knockdown MDA-MB-231 cells led to decreased invasion. RNAi-mediated suppression of Reelin in α3 knockdown MDA-MB-231 cells mitigated this effect of conditioned-medium, identifying secreted Reelin as an inhibitor of cell invasion. These results demonstrate a novel role for α3β1 in repressing Reelin in breast cancer cells to promote invasion, supporting this integrin as a potential therapeutic target. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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16 pages, 5300 KiB

Open AccessArticle

Fibronectin-Expressing Mesenchymal Tumor Cells Promote Breast Cancer Metastasis

by Brian H. Jun, Tianqi Guo, Sarah Libring, Monica K. Chanda, Juan Sebastian Paez, Aparna Shinde, Michael K. Wendt, Pavlos P. Vlachos and Luis Solorio

Cancers 2020, 12(9), 2553; https://doi.org/10.3390/cancers12092553 - 8 Sep 2020

Cited by 23 | Viewed by 5213

Abstract

Tumor metastasis is connected to epithelial-mesenchymal heterogeneity (EMH) and the extracellular matrix (ECM) within the tumor microenvironment. Mesenchymal-like fibronectin (FN) expressing tumor cells enhance metastasis within tumors that have EMH. However, the secondary tumors are primarily composed of the FN null population. Interestingly, [...] Read more.

Tumor metastasis is connected to epithelial-mesenchymal heterogeneity (EMH) and the extracellular matrix (ECM) within the tumor microenvironment. Mesenchymal-like fibronectin (FN) expressing tumor cells enhance metastasis within tumors that have EMH. However, the secondary tumors are primarily composed of the FN null population. Interestingly, during tumor cell dissemination, the invasive front has more mesenchymal-like characteristics, although the outgrowths of metastatic colonies consist of a more epithelial-like population of cells. We hypothesize that soluble FN provided by mesenchymal-like tumor cells plays a role in supporting the survival of the more epithelial-like tumor cells within the metastatic niche in a paracrine manner. Furthermore, due to a lower rate of proliferation, the mesenchymal-like tumor cells become a minority population within the metastatic niche. In this study, we utilized a multi-parametric cell-tracking algorithm and immunoblotting to evaluate the effect of EMH on the growth and invasion of an isogenic cell series within a 3D collagen network using a microfluidic platform. Using the MCF10A progression series, we demonstrated that co-culture with FN-expressing MCF10CA1h cells significantly enhanced the survival of the more epithelial MCF10CA1a cells, with a two-fold increase in the population after 5 days in co-culture, whereas the population of the MCF10CA1a cells began to decrease after 2.5 days when cultured alone (p < 0.001). However, co-culture did not significantly alter the rate of proliferation for the more mesenchymal MCF10CA1h cells. Epithelial tumor cells not only showed prolonged survival, but migrated significantly longer distances (350 µm compared with 150 µm, respectively, p < 0.01) and with greater velocity magnitude (4.5 µm/h compared with 2.1 µm/h, respectively, p < 0.001) under co-culture conditions and in response to exogenously administered FN. Genetic depletion of FN from the MCF10CA1h cells resulted in a loss of survival and migration capacity of the epithelial and mesenchymal populations. These data suggest that mesenchymal tumor cells may function to support the survival and outgrowth of more epithelial tumor cells within the metastatic niche and that inhibition of FN production may provide a valuable target for treating metastatic disease. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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Review

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22 pages, 921 KiB

Open AccessReview

Context Matters: Response Heterogeneity to Collagen-Targeting Approaches in Desmoplastic Cancers

by Ashley M. Fuller and Tzipora S. Karin Eisinger-Mathason

Cancers 2022, 14(13), 3132; https://doi.org/10.3390/cancers14133132 - 26 Jun 2022

Cited by 11 | Viewed by 3251

Abstract

The deposition of collagen-rich desmoplastic tissue is a well-documented feature of the solid tumor microenvironment (TME). However, efforts to target the desmoplastic extracellular matrix (ECM) en masse, or collagen molecules more specifically, have been met with mixed and sometimes paradoxical results. In this [...] Read more.

The deposition of collagen-rich desmoplastic tissue is a well-documented feature of the solid tumor microenvironment (TME). However, efforts to target the desmoplastic extracellular matrix (ECM) en masse, or collagen molecules more specifically, have been met with mixed and sometimes paradoxical results. In this review, we posit that these discrepancies are due—at least in part—to the incredible diversity of the collagen superfamily. Specifically, whereas studies of “collagen-targeting” approaches frequently refer to “collagen” as a single molecule or relatively homogeneous molecular family, 28 individual collagens have been identified in mammalian tissues, each with a unique structure, supramolecular assembly pattern, tissue distribution, and/or function. Moreover, some collagen species have been shown to exert both pro- and anti-neoplastic effects in the desmoplastic TME, even within the same cancer type. Therefore, herein, we describe the diversity of the collagen family in normal tissues and highlight the context-specific roles of individual collagen molecules in desmoplastic tumors. We further discuss how this heterogeneity relates to the variable efficacy of “collagen-targeting” strategies in this setting and provide guidance for future directions in the field. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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17 pages, 1483 KiB

Open AccessReview

Potential Therapeutic Significance of Laminin in Head and Neck Squamous Carcinomas

by Nathalia Meireles Da Costa, Fábio A. Mendes, Bruno Pontes, Luiz Eurico Nasciutti, Luis Felipe Ribeiro Pinto and Antonio Palumbo Júnior

Cancers 2021, 13(8), 1890; https://doi.org/10.3390/cancers13081890 - 15 Apr 2021

Cited by 22 | Viewed by 3793

Abstract

Head and neck squamous cell carcinomas (HNSCC) are among the most common and lethal tumors worldwide, occurring mostly in oral cavity, pharynx, and larynx tissues. The squamous epithelia homeostasis is supported by the extracellular matrix (ECM), and alterations in this compartment are crucial [...] Read more.

Head and neck squamous cell carcinomas (HNSCC) are among the most common and lethal tumors worldwide, occurring mostly in oral cavity, pharynx, and larynx tissues. The squamous epithelia homeostasis is supported by the extracellular matrix (ECM), and alterations in this compartment are crucial for cancer development and progression. Laminin is a fundamental component of ECM, where it represents one of the main components of basement membrane (BM), and data supporting its contribution to HNSCC genesis and progression has been vastly explored in oral cavity squamous cell carcinoma. Laminin subtypes 111 (LN-111) and 332 (LN-332) are the main isoforms associated with malignant transformation, contributing to proliferation, adhesion, migration, invasion, and metastasis, due to its involvement in the regulation of several pathways associated with HNSCC carcinogenesis, including the activation of the EGFR/MAPK signaling pathway. Therefore, it draws attention to the possibility that laminin may represent a convergence point in HNSCC natural history, and an attractive potential therapeutic target for these tumors. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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25 pages, 9574 KiB

Open AccessEditor’s ChoiceReview

Targeting Lysyl Oxidase Family Meditated Matrix Cross-Linking as an Anti-Stromal Therapy in Solid Tumours

by Yordanos F.I. Setargew, Kaitlin Wyllie, Rhiannon D. Grant, Jessica L. Chitty and Thomas R. Cox

Cancers 2021, 13(3), 491; https://doi.org/10.3390/cancers13030491 - 27 Jan 2021

Cited by 65 | Viewed by 9709

Abstract

The lysyl oxidase (LOX) family of enzymes are a major driver in the biogenesis of desmoplastic matrix at the primary tumour and secondary metastatic sites. With the increasing interest in and development of anti-stromal therapies aimed at improving clinical outcomes of cancer patients, [...] Read more.

The lysyl oxidase (LOX) family of enzymes are a major driver in the biogenesis of desmoplastic matrix at the primary tumour and secondary metastatic sites. With the increasing interest in and development of anti-stromal therapies aimed at improving clinical outcomes of cancer patients, the Lox family has emerged as a potentially powerful clinical target. This review examines how lysyl oxidase family dysregulation in solid cancers contributes to disease progression and poor patient outcomes, as well as an evaluation of the preclinical landscape of LOX family targeting therapeutics. We also discuss the suitability of the LOX family as a diagnostic and/or prognostic marker in solid tumours. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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25 pages, 9656 KiB

Open AccessReview

Cancer Extracellular Matrix Proteins Regulate Tumour Immunity

by Alex Gordon-Weeks and Arseniy E. Yuzhalin

Cancers 2020, 12(11), 3331; https://doi.org/10.3390/cancers12113331 - 11 Nov 2020

Cited by 77 | Viewed by 6166

Abstract

The extracellular matrix (ECM) plays an increasingly recognised role in the development and progression of cancer. Whilst significant progress has been made in targeting aspects of the tumour microenvironment such as tumour immunity and angiogenesis, there are no therapies that address the cancer [...] Read more.

The extracellular matrix (ECM) plays an increasingly recognised role in the development and progression of cancer. Whilst significant progress has been made in targeting aspects of the tumour microenvironment such as tumour immunity and angiogenesis, there are no therapies that address the cancer ECM. Importantly, immune function relies heavily on the structure, physics and composition of the ECM, indicating that cancer ECM and immunity are mechanistically inseparable. In this review we highlight mechanisms by which the ECM shapes tumour immunity, identifying potential therapeutic targets within the ECM. These data indicate that to fully realise the potential of cancer immunotherapy, the cancer ECM requires simultaneous consideration. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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17 pages, 1295 KiB

Open AccessReview

Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded

by Kousik Kesh, Vineet K. Gupta, Brittany Durden, Vanessa Garrido, Beatriz Mateo-Victoriano, Shweta P. Lavania and Sulagna Banerjee

Cancers 2020, 12(10), 3067; https://doi.org/10.3390/cancers12103067 - 21 Oct 2020

Cited by 55 | Viewed by 5691

Abstract

The extracellular matrix (ECM) has remained an enigmatic component of the tumor microenvironment. It drives metastasis via its interaction with the integrin signaling pathway, contributes to tumor progression and confers therapy resistance by providing a physical barrier around the tumor. The complexity of [...] Read more.

The extracellular matrix (ECM) has remained an enigmatic component of the tumor microenvironment. It drives metastasis via its interaction with the integrin signaling pathway, contributes to tumor progression and confers therapy resistance by providing a physical barrier around the tumor. The complexity of the ECM lies in its heterogeneous composition and complex glycosylation that can provide a support matrix as well as trigger oncogenic signaling pathways by interacting with the tumor cells. In this review, we attempt to dissect the role of the ECM in enriching for the treatment refractory cancer stem cell population and how it may be involved in regulating their metabolic needs. Additionally, we discuss how the ECM is instrumental in remodeling the tumor immune microenvironment and the potential ways to target this component in order to develop a viable therapy. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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