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Open AccessEditorial

What Is the Fuss about Integrins and the Tumor Microenvironment?

by Johannes A. Eble and Donald Gullberg

Cancers 2019, 11(9), 1296; https://doi.org/10.3390/cancers11091296 - 3 Sep 2019

Cited by 3 | Viewed by 2822

Abstract

In recent years the tumor microenvironment (TME) has received increasing attention [...] Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

Research

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21 pages, 8763 KiB

Open AccessArticle

α11β1 Integrin is Induced in a Subset of Cancer-Associated Fibroblasts in Desmoplastic Tumor Stroma and Mediates In Vitro Cell Migration

by Cédric Zeltz, Jahedul Alam, Hengshuo Liu, Pugazendhi M. Erusappan, Heinz Hoschuetzky, Anders Molven, Himalaya Parajuli, Edna Cukierman, Daniela-Elena Costea, Ning Lu and Donald Gullberg

Cancers 2019, 11(6), 765; https://doi.org/10.3390/cancers11060765 - 1 Jun 2019

Cited by 60 | Viewed by 7346

Abstract

Integrin α11β1 is a collagen receptor that has been reported to be overexpressed in the stroma of non-small cell lung cancer (NSCLC) and of head and neck squamous cell carcinoma (HNSCC). In the current study, we further analyzed integrin α11 expression in 14 [...] Read more.

Integrin α11β1 is a collagen receptor that has been reported to be overexpressed in the stroma of non-small cell lung cancer (NSCLC) and of head and neck squamous cell carcinoma (HNSCC). In the current study, we further analyzed integrin α11 expression in 14 tumor types by screening a tumor tissue array while using mAb 203E3, a newly developed monoclonal antibody to human α11. Different degrees of expression of integrin α11 were observed in the stroma of breast, ovary, skin, lung, uterus, stomach, and pancreatic ductal adenocarcinoma (PDAC) tumors. Co-expression queries with the myofibroblastic cancer-associated fibroblast (myCAF) marker, alpha smooth muscle actin (αSMA), demonstrated a moderate level of α11⁺ in myCAFs associated with PDAC and HNSCC tumors, and a lack of α11 expression in additional stromal cells (i.e., cells positive for fibroblast-specific protein 1 (FSP1) and NG2). The new function-blocking α11 antibody, mAb 203E1, inhibited cell adhesion to collagen I, partially hindered fibroblast-mediated collagen remodeling and obstructed the three-dimensional (3D) migration rates of PDAC myCAFs. Our data demonstrate that integrin α11 is expressed in a subset of non-pericyte-derived CAFs in a range of cancers and suggest that α11β1 constitutes an important receptor for collagen remodeling and CAF migration in the tumor microenvironment (TME). Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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16 pages, 4083 KiB

Open AccessArticle

LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity

by Cédric Zeltz, Elena Pasko, Thomas R. Cox, Roya Navab and Ming-Sound Tsao

Cancers 2019, 11(5), 705; https://doi.org/10.3390/cancers11050705 - 22 May 2019

Cited by 44 | Viewed by 5656

Abstract

Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, [...] Read more.

Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells. Using cancer-associated fibroblast (CAF) with either a knockdown or overexpression of LOXL1, we demonstrated a role for LOXL1 in collagen matrix remodeling and collagen fiber alignment in vitro and in vivo in a NSCLC xenograft model. As a consequence of collagen reorganization in NSCLC tumor stroma, we showed that LOXL1 supported tumor growth and progression. Our findings demonstrate that stromal LOXL1, under regulation of integrin α11, is a determinant factor of NSCLC tumorigenesis and may be an interesting target in this disease. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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17 pages, 4148 KiB

Open AccessEditor’s ChoiceArticle

CAR T-Cells Targeting the Integrin αvβ6 and Co-Expressing the Chemokine Receptor CXCR2 Demonstrate Enhanced Homing and Efficacy against Several Solid Malignancies

by Lynsey M. Whilding, Leena Halim, Benjamin Draper, Ana C. Parente-Pereira, Tomasz Zabinski, David Marc Davies and John Maher

Cancers 2019, 11(5), 674; https://doi.org/10.3390/cancers11050674 - 14 May 2019

Cited by 144 | Viewed by 9837

Abstract

Despite the unprecedented clinical success of chimeric antigen receptors (CAR) T-cells against haematological malignancy, solid tumors impose a far greater challenge to success. Largely, this stems from an inadequate capacity of CAR T-cells that can traffic and maintain function within a hostile microenvironment. [...] Read more.

Despite the unprecedented clinical success of chimeric antigen receptors (CAR) T-cells against haematological malignancy, solid tumors impose a far greater challenge to success. Largely, this stems from an inadequate capacity of CAR T-cells that can traffic and maintain function within a hostile microenvironment. To enhance tumor-directed T-cell trafficking, we have engineered CAR T-cells to acquire heightened responsiveness to interleukin (IL)-8. Circulating IL-8 levels correlate with disease burden and prognosis in multiple solid tumors in which it exerts diverse pathological functions including angiogenesis, support of cancer stem cell survival, and recruitment of immunosuppressive myeloid cells. To harness tumor-derived IL-8 for therapeutic benefit, we have co-expressed either of its cognate receptors (CXCR1 or CXCR2) in CAR T-cells that target the tumor-associated αvβ6 integrin. We demonstrate here that CXCR2-expressing CAR T-cells migrate more efficiently towards IL-8 and towards tumor conditioned media that contains this cytokine. As a result, these CAR T-cells elicit superior anti-tumor activity against established αvβ6-expressing ovarian or pancreatic tumor xenografts, with a more favorable toxicity profile. These data support the further engineering of CAR T-cells to acquire responsiveness to cancer-derived chemokines in order to improve their therapeutic activity against solid tumors. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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12 pages, 1621 KiB

Open AccessArticle

High Mannose Binding Lectin (PFL) from Pseudomonas fluorescens Down-Regulates Cancer-Associated Integrins and Immune Checkpoint Ligand B7-H4

by Yuichiro Sato, Kiminori Matsubara, Takanori Kubo, Hirobumi Sunayama, Yuta Hatori, Kinjiro Morimoto and Toshio Seyama

Cancers 2019, 11(5), 604; https://doi.org/10.3390/cancers11050604 - 30 Apr 2019

Cited by 5 | Viewed by 3694

Abstract

Pseudomonas fluorescens lectin (PFL), which belongs to the high mannose (HM)-binding OAAH (Oscillatoria agardhii agglutinin homologue) lectin family, induces cancer cell death. However, the detailed mechanisms underlying this process have not yet been elucidated. We found that PFL decreased various integrins as [...] Read more.

Pseudomonas fluorescens lectin (PFL), which belongs to the high mannose (HM)-binding OAAH (Oscillatoria agardhii agglutinin homologue) lectin family, induces cancer cell death. However, the detailed mechanisms underlying this process have not yet been elucidated. We found that PFL decreased various integrins as well as EGFR in cancer cells by promoting internalization and autophagic degradation of these molecules, subsequently inducing caspase-8 dependent cell apoptosis. As revealed by an ex vivo angiogenesis assay using the rat aortic model, PFL inhibited neovascularization in a dose-dependent manner, which was potentially mediated by down-regulation of endothelium integrins. Interestingly, PFL also down-regulated B7-H4 in cancer cells, which has been implicated as a negative regulator of T cell-mediated immunity. We found that B7-H4 co-localized with β3 integrin in MKN28 gastric cancer cells. siRNA silencing of B7-H4 in MKN28 cells decreased expression of β3 integrin, suggesting physical and functional association between these molecules. Direct interaction of PFL with integrin αvβ3 or B7-H4 was examined by surface plasmon resonance analysis, which detected high affinity glycan-dependent binding to PFL. These investigations suggest that PFL interaction with cell surface integrins is a key process for the anti-cancer activities of PFL. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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24 pages, 4356 KiB

Open AccessArticle

Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival

by Matilda Munksgaard Thorén, Katarzyna Chmielarska Masoumi, Cecilia Krona, Xiaoli Huang, Soumi Kundu, Linnéa Schmidt, Karin Forsberg-Nilsson, Marcus Floyd Keep, Elisabet Englund, Sven Nelander, Bo Holmqvist and Evy Lundgren-Åkerlund

Cancers 2019, 11(4), 587; https://doi.org/10.3390/cancers11040587 - 25 Apr 2019

Cited by 30 | Viewed by 6479

Abstract

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 [...] Read more.

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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13 pages, 2516 KiB

Open AccessArticle

Efficacy of a Selective Binder of α_Vβ₃ Integrin Linked to the Tyrosine Kinase Inhibitor Sunitinib in Ovarian Carcinoma Preclinical Models

by Andrea Sartori, Cristina Corno, Michelandrea De Cesare, Eugenio Scanziani, Lucia Minoli, Lucia Battistini, Franca Zanardi and Paola Perego

Cancers 2019, 11(4), 531; https://doi.org/10.3390/cancers11040531 - 13 Apr 2019

Cited by 18 | Viewed by 3805

Abstract

Ovarian carcinoma, the most lethal gynecological cancer, is characterized by late diagnosis, with drug resistance limiting the efficacy of platinum-based therapy. Since some integrins are upregulated in cancer, including ovarian carcinoma, they represent a potential target for drug delivery. Receptor tyrosine kinases are [...] Read more.

Ovarian carcinoma, the most lethal gynecological cancer, is characterized by late diagnosis, with drug resistance limiting the efficacy of platinum-based therapy. Since some integrins are upregulated in cancer, including ovarian carcinoma, they represent a potential target for drug delivery. Receptor tyrosine kinases are also deregulated in cancer and their expression has been associated with drug resistance. Here, the antitumor effects of three conjugates possessing a selective binder of the extracellular portion of integrin α_Vβ₃ covalently linked to the tyrosine kinase inhibitor sunitinib were investigated in cisplatin-sensitive and -resistant ovarian carcinoma cells expressing both tyrosine kinase VEGFR2 and α_Vβ₃ at different levels. We found that one of the three compounds was active in inhibiting the growth of both drug-sensitive and -resistant cells in the micromolar range with a slightly increased potency in resistant cells as compared to sunitinib. The same compound markedly impaired cell migratory and invasive abilities and reduced paxillin phosphorylation. Antitumor activity studies in IGROV-1/Pt1 cells xenografted in nude mice revealed a striking activity of this conjugate versus sunitinib. Taken together, our results support the interest of integrin-targeted sunitinib conjugates for the treatment of drug-resistant tumors. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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20 pages, 3127 KiB

Open AccessArticle

The Interaction between Laminin-332 and α3β1 Integrin Determines Differentiation and Maintenance of CAFs, and Supports Invasion of Pancreatic Duct Adenocarcinoma Cells

by Ana C. Martins Cavaco, Maryam Rezaei, Michele F. Caliandro, Augusto Martins Lima, Martin Stehling, Sameer A. Dhayat, Jörg Haier, Cord Brakebusch and Johannes A. Eble

Cancers 2019, 11(1), 14; https://doi.org/10.3390/cancers11010014 - 21 Dec 2018

Cited by 48 | Viewed by 6150

Abstract

Ranking among the most lethal tumour entities, pancreatic duct adenocarcinoma cells invade neighbouring tissue resulting in high incidence of metastasis. They are supported by tumour stroma fibroblasts which have undergone differentiation into cancer-associated fibroblasts (CAFs). Stiffness of cell substratum, cytokines, such as transforming [...] Read more.

Ranking among the most lethal tumour entities, pancreatic duct adenocarcinoma cells invade neighbouring tissue resulting in high incidence of metastasis. They are supported by tumour stroma fibroblasts which have undergone differentiation into cancer-associated fibroblasts (CAFs). Stiffness of cell substratum, cytokines, such as transforming growth factor-β (TGF-β), and stromal matrix proteins, such as laminin-332, are factors which promote CAF differentiation. In a spheroid culture system, differentiation of CAFs was analysed for laminin-332 production, laminin-binding integrin repertoire, adhesion and migration behaviour, and, in heterospheroids, for their interplay with the pancreatic duct adenocarcinoma AsPC-I cells. Our data reveal that CAFs produce laminin-332 thus contributing to its ectopic deposition within the tumour stroma. Moreover, CAF differentiation correlates with an increased expression of α3β1 integrin, the principal laminin-332-receptor. Beyond its role as novel CAF marker protein, integrin α3β1 crucially determines differentiation and maintenance of the CAF phenotype, as knock-out of the integrin α3 subunit reversed the CAF differentiated state. AsPC-I cells co-cultured in heterospheroids with integrin α3-deficient CAFs invaded less than from heterospheroids with wild-type CAFs. This study highlights the role of integrin α3β1 integrin-laminin-332 interaction of CAFs which promotes and sustains differentiation of CAFs and promotes carcinoma invasion. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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Review

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24 pages, 1583 KiB

Open AccessReview

Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment

by Nicholas F. Brown and John F. Marshall

Cancers 2019, 11(9), 1221; https://doi.org/10.3390/cancers11091221 - 21 Aug 2019

Cited by 77 | Viewed by 10487

Abstract

TGFβ (transforming growth factor-beta) is a pleotropic cytokine with contrasting effects in cancer. In normal tissue and early tumours, TGFβ acts as a tumour suppressor, limiting proliferation and inducing apoptosis. However, these effects are eventually abrogated by the loss or inactivation of downstream [...] Read more.

TGFβ (transforming growth factor-beta) is a pleotropic cytokine with contrasting effects in cancer. In normal tissue and early tumours, TGFβ acts as a tumour suppressor, limiting proliferation and inducing apoptosis. However, these effects are eventually abrogated by the loss or inactivation of downstream signalling within the TGFβ pathway, and in established tumours, TGFβ then acts as a tumour promotor through multiple mechanisms including inducing epithelial-to-mesenchymal transition (EMT), promoting formation of cancer-associated fibroblasts (CAFs) and increasing angiogenesis. TGFβ is secrereted as a large latent complex and is embedded in the extracellular matrix or held on the surface of cells and must be activated before mediating its multiple functions. Thus, whilst TGFβ is abundant in the tumour microenvironment (TME), its functionality is regulated by local activation. The αv-integrins are major activators of latent-TGFβ. The potential benefits of manipulating the immune TME have been highlighted by the clinical success of immune-checkpoint inhibitors in a number of solid tumour types. TGFβ is a potent suppressor of T-cell-mediated immune surveillance and a key cause of resistance to checkpoint inhibitors. Therefore, as certain integrins locally activate TGFβ, they are likely to have a role in the immunosuppressive TME, although this remains to be confirmed. In this review, we discussed the role of TGFβ in cancer, the role of integrins in activating TGFβ in the TME, and the potential benefits of targeting integrins to augment immunotherapies. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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30 pages, 1095 KiB

Open AccessReview

Are Integrins Still Practicable Targets for Anti-Cancer Therapy?

by Begoña Alday-Parejo, Roger Stupp and Curzio Rüegg

Cancers 2019, 11(7), 978; https://doi.org/10.3390/cancers11070978 - 12 Jul 2019

Cited by 127 | Viewed by 14612

Abstract

Correlative clinical evidence and experimental observations indicate that integrin adhesion receptors, in particular those of the αV family, are relevant to cancer cell features, including proliferation, survival, migration, invasion, and metastasis. In addition, integrins promote events in the tumor microenvironment that are critical [...] Read more.

Correlative clinical evidence and experimental observations indicate that integrin adhesion receptors, in particular those of the αV family, are relevant to cancer cell features, including proliferation, survival, migration, invasion, and metastasis. In addition, integrins promote events in the tumor microenvironment that are critical for tumor progression and metastasis, including tumor angiogenesis, matrix remodeling, and the recruitment of immune and inflammatory cells. In spite of compelling preclinical results demonstrating that the inhibition of integrin αVβ3/αVβ5 and α5β1 has therapeutic potential, clinical trials with integrin inhibitors targeting those integrins have repeatedly failed to demonstrate therapeutic benefits in cancer patients. Here, we review emerging integrin functions and their proposed contribution to tumor progression, discuss preclinical evidence of therapeutic significance, revisit clinical trial results, and consider alternative approaches for their therapeutic targeting in oncology, including targeting integrins in the other cells of the tumor microenvironment, e.g., cancer-associated fibroblasts and immune/inflammatory cells. We conclude that integrins remain a valid target for cancer therapy; however, agents with better pharmacological properties, alternative models for their preclinical evaluation, and innovative combination strategies for clinical testing (e.g., together with immuno-oncology agents) are needed. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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17 pages, 2854 KiB

Open AccessReview

Interplay Between LOX Enzymes and Integrins in the Tumor Microenvironment

by Pier Giorgio Amendola, Raphael Reuten and Janine Terra Erler

Cancers 2019, 11(5), 729; https://doi.org/10.3390/cancers11050729 - 26 May 2019

Cited by 51 | Viewed by 7123

Abstract

Members of the lysyl oxidase (LOX) family are secreted copper-dependent amine oxidases that catalyze the covalent crosslinking of collagens and elastin in the extracellular matrix (ECM), an essential process for the structural integrity of all tissues. LOX enzymes can also remodel the tumor [...] Read more.

Members of the lysyl oxidase (LOX) family are secreted copper-dependent amine oxidases that catalyze the covalent crosslinking of collagens and elastin in the extracellular matrix (ECM), an essential process for the structural integrity of all tissues. LOX enzymes can also remodel the tumor microenvironment and have been implicated in all stages of tumor initiation and progression of many cancer types. Changes in the ECM can influence several cancer cell phenotypes. Integrin adhesion complexes (IACs) physically connect cells with their microenvironment. This review article summarizes the main findings on the role of LOX proteins in modulating the tumor microenvironment, with a particular focus on how ECM changes are integrated by IACs to modulate cells behavior. Finally, we discuss how the development of selective LOX inhibitors may lead to novel and effective therapies in cancer treatment. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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17 pages, 446 KiB

Open AccessEditor’s ChoiceReview

Integrins, CAFs and Mechanical Forces in the Progression of Cancer

by Imjoo Jang and Karen A. Beningo

Cancers 2019, 11(5), 721; https://doi.org/10.3390/cancers11050721 - 24 May 2019

Cited by 118 | Viewed by 12242

Abstract

Cells respond to both chemical and mechanical cues present within their microenvironment. Various mechanical signals are detected by and transmitted to the cells through mechanoreceptors. These receptors often contact with the extracellular matrix (ECM), where the external signals are converted into a physiological [...] Read more.

Cells respond to both chemical and mechanical cues present within their microenvironment. Various mechanical signals are detected by and transmitted to the cells through mechanoreceptors. These receptors often contact with the extracellular matrix (ECM), where the external signals are converted into a physiological response. Integrins are well-defined mechanoreceptors that physically connect the actomyosin cytoskeleton to the surrounding matrix and transduce signals. Families of α and β subunits can form a variety of heterodimers that have been implicated in cancer progression and differ among types of cancer. These heterodimers serve as the nexus of communication between the cells and the tumor microenvironment (TME). The TME is dynamic and composed of stromal cells, ECM and associated soluble factors. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs). Accumulating studies implicate CAFs in cancer development and metastasis through their remodeling of the ECM and release of large amounts of ECM proteins and soluble factors. Considering that the communication between cancer cells and CAFs, in large part, takes place through the ECM, the involvement of integrins in the crosstalk is significant. This review discusses the role of integrins, as the primary cell-ECM mechanoreceptors, in cancer progression, highlighting integrin-mediated mechanical communication between cancer cells and CAFs. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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13 pages, 5205 KiB

Open AccessReview

Integrin Regulation of CAF Differentiation and Function

by C. Michael DiPersio and Livingston Van De Water

Cancers 2019, 11(5), 715; https://doi.org/10.3390/cancers11050715 - 24 May 2019

Cited by 21 | Viewed by 5083

Abstract

Extensive remodeling of the extracellular matrix, together with paracrine communication between tumor cells and stromal cells, contribute to an “activated” tumor microenvironment that supports malignant growth and progression. These stromal cells include inflammatory cells, endothelial cells, and cancer-associated fibroblasts (CAFs). Integrins are expressed [...] Read more.

Extensive remodeling of the extracellular matrix, together with paracrine communication between tumor cells and stromal cells, contribute to an “activated” tumor microenvironment that supports malignant growth and progression. These stromal cells include inflammatory cells, endothelial cells, and cancer-associated fibroblasts (CAFs). Integrins are expressed on all tumor and stromal cell types where they regulate both cell adhesion and bidirectional signal transduction across the cell membrane. In this capacity, integrins control pro-tumorigenic cell autonomous functions such as growth and survival, as well as paracrine crosstalk between tumor cells and stromal cells. The myofibroblast-like properties of cancer-associated fibroblasts (CAFs), such as robust contractility and extracellular matrix (ECM) deposition, allow them to generate both chemical and mechanical signals that support invasive tumor growth. In this review, we discuss the roles of integrins in regulating the ability of CAFs to generate and respond to extracellular cues in the tumor microenvironment. Since functions of specific integrins in CAFs are only beginning to emerge, we take advantage of a more extensive literature on how integrins regulate wound myofibroblast differentiation and function, as some of these integrin functions are likely to extrapolate to CAFs within the tumor microenvironment. In addition, we discuss the roles that integrins play in controlling paracrine signals that emanate from epithelial/tumor cells to stimulate fibroblasts/CAFs. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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27 pages, 2293 KiB

Open AccessReview

Role of Integrins in Resistance to Therapies Targeting Growth Factor Receptors in Cancer

by Elisabete Cruz da Silva, Monique Dontenwill, Laurence Choulier and Maxime Lehmann

Cancers 2019, 11(5), 692; https://doi.org/10.3390/cancers11050692 - 17 May 2019

Cited by 52 | Viewed by 8924

Abstract

Integrins contribute to cancer progression and aggressiveness by activating intracellular signal transduction pathways and transducing mechanical tension forces. Remarkably, these adhesion receptors share common signaling networks with receptor tyrosine kinases (RTKs) and support their oncogenic activity, thereby promoting cancer cell proliferation, survival and [...] Read more.

Integrins contribute to cancer progression and aggressiveness by activating intracellular signal transduction pathways and transducing mechanical tension forces. Remarkably, these adhesion receptors share common signaling networks with receptor tyrosine kinases (RTKs) and support their oncogenic activity, thereby promoting cancer cell proliferation, survival and invasion. During the last decade, preclinical studies have revealed that integrins play an important role in resistance to therapies targeting RTKs and their downstream pathways. A remarkable feature of integrins is their wide-ranging interconnection with RTKs, which helps cancer cells to adapt and better survive therapeutic treatments. In this context, we should consider not only the integrins expressed in cancer cells but also those expressed in stromal cells, since these can mechanically increase the rigidity of the tumor microenvironment and confer resistance to treatment. This review presents some of these mechanisms and outlines new treatment options for improving the efficacy of therapies targeting RTK signaling. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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26 pages, 1660 KiB

Open AccessEditor’s ChoiceReview

Breast Cancer Tumor Stroma: Cellular Components, Phenotypic Heterogeneity, Intercellular Communication, Prognostic Implications and Therapeutic Opportunities

by Noemi Eiro, Luis O. Gonzalez, María Fraile, Sandra Cid, Jose Schneider and Francisco J. Vizoso

Cancers 2019, 11(5), 664; https://doi.org/10.3390/cancers11050664 - 13 May 2019

Cited by 79 | Viewed by 7941

Abstract

Although the mechanisms underlying the genesis and progression of breast cancer are better understood than ever, it is still the most frequent malignant tumor in women and one of the leading causes of cancer death. Therefore, we need to establish new approaches that [...] Read more.

Although the mechanisms underlying the genesis and progression of breast cancer are better understood than ever, it is still the most frequent malignant tumor in women and one of the leading causes of cancer death. Therefore, we need to establish new approaches that lead us to better understand the prognosis of this heterogeneous systemic disease and to propose new therapeutic strategies. Cancer is not only a malignant transformation of the epithelial cells merely based on their autonomous or acquired proliferative capacity. Today, data support the concept of cancer as an ecosystem based on a cellular sociology, with diverse components and complex interactions between them. Among the different cell types that make up the stroma, which have a relevant role in the dynamics of tumor/stromal cell interactions, the main ones are cancer associated fibroblasts, endothelial cells, immune cells and mesenchymal stromal cells. Several factors expressed by the stroma of breast carcinomas are associated with the development of metastasis, such as matrix metalloproteases, their tissular inhibitors or some of their regulators like integrins, cytokines or toll-like receptors. Based on the expression of these factors, two types of breast cancer stroma can be proposed with significantly different influence on the prognosis of patients. In addition, there is evidence about the existence of bi-directional signals between cancer cells and tumor stroma cells with prognostic implications, suggesting new therapeutic strategies in breast cancer. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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30 pages, 866 KiB

Open AccessReview

Integrins: Moonlighting Proteins in Invadosome Formation

by Rafael Peláez, Ana Pariente, Álvaro Pérez-Sala and Ignacio M. Larrayoz

Cancers 2019, 11(5), 615; https://doi.org/10.3390/cancers11050615 - 2 May 2019

Cited by 28 | Viewed by 6215

Abstract

Invadopodia are actin-rich protrusions developed by transformed cells in 2D/3D environments that are implicated in extracellular matrix (ECM) remodeling and degradation. These structures have an undoubted association with cancer invasion and metastasis because invadopodium formation in vivo is a key step for intra/extravasation [...] Read more.

Invadopodia are actin-rich protrusions developed by transformed cells in 2D/3D environments that are implicated in extracellular matrix (ECM) remodeling and degradation. These structures have an undoubted association with cancer invasion and metastasis because invadopodium formation in vivo is a key step for intra/extravasation of tumor cells. Invadopodia are closely related to other actin-rich structures known as podosomes, which are typical structures of normal cells necessary for different physiological processes during development and organogenesis. Invadopodia and podosomes are included in the general term ‘invadosomes,’ as they both appear as actin puncta on plasma membranes next to extracellular matrix metalloproteinases, although organization, regulation, and function are slightly different. Integrins are transmembrane proteins implicated in cell–cell and cell–matrix interactions and other important processes such as molecular signaling, mechano-transduction, and cell functions, e.g., adhesion, migration, or invasion. It is noteworthy that integrin expression is altered in many tumors, and other pathologies such as cardiovascular or immune dysfunctions. Over the last few years, growing evidence has suggested a role of integrins in the formation of invadopodia. However, their implication in invadopodia formation and adhesion to the ECM is still not well known. This review focuses on the role of integrins in invadopodium formation and provides a general overview of the involvement of these proteins in the mechanisms of metastasis, taking into account classic research through to the latest and most advanced work in the field. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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