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TGF-β Signaling in Gastrointestinal Cancers: Progress in Basic and Clinical Research

by Takehiko Yokobori and Masahiko Nishiyama

J. Clin. Med. 2017, 6(1), 11; https://doi.org/10.3390/jcm6010011 - 18 Jan 2017

Cited by 34 | Viewed by 7722

Transforming growth factor (TGF)-β superfamily proteins have many important biological functions, including regulation of tissue differentiation, cell proliferation, and migration in both normal and cancer cells. Many studies have reported that TGF-β signaling is associated with disease progression and therapeutic resistance in several [...] Read more.

Transforming growth factor (TGF)-β superfamily proteins have many important biological functions, including regulation of tissue differentiation, cell proliferation, and migration in both normal and cancer cells. Many studies have reported that TGF-β signaling is associated with disease progression and therapeutic resistance in several cancers. Similarly, TGF-β-induced protein (TGFBI)—a downstream component of the TGF-β signaling pathway—has been shown to promote and/or inhibit cancer. Here, we review the state of basic and clinical research on the roles of TGF-β and TGFBI in gastrointestinal cancers. Full article

(This article belongs to the Special Issue Biological and Clinical Aspects of TGF-beta in Carcinogenesis)

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Mammary Gland Involution Provides a Unique Model to Study the TGF-β Cancer Paradox

by Qiuchen Guo, Courtney Betts, Nathan Pennock, Elizabeth Mitchell and Pepper Schedin

J. Clin. Med. 2017, 6(1), 10; https://doi.org/10.3390/jcm6010010 - 13 Jan 2017

Cited by 22 | Viewed by 9589

Abstract

Transforming Growth Factor-β (TGF-β) signaling in cancer has been termed the “TGF-β paradox”, acting as both a tumor suppresser and promoter. The complexity of TGF-β signaling within the tumor is context dependent, and greatly impacted by cellular crosstalk between TGF-β responsive cells in [...] Read more.

Transforming Growth Factor-β (TGF-β) signaling in cancer has been termed the “TGF-β paradox”, acting as both a tumor suppresser and promoter. The complexity of TGF-β signaling within the tumor is context dependent, and greatly impacted by cellular crosstalk between TGF-β responsive cells in the microenvironment including adjacent epithelial, endothelial, mesenchymal, and hematopoietic cells. Here we utilize normal, weaning-induced mammary gland involution as a tissue microenvironment model to study the complexity of TGF-β function. This article reviews facets of mammary gland involution that are TGF-β regulated, namely mammary epithelial cell death, immune activation, and extracellular matrix remodeling. We outline how distinct cellular responses and crosstalk between cell types during physiologically normal mammary gland involution contribute to simultaneous tumor suppressive and promotional microenvironments. We also highlight alternatives to direct TGF-β blocking anti-cancer therapies with an emphasis on eliciting concerted microenvironmental-mediated tumor suppression. Full article

(This article belongs to the Special Issue Biological and Clinical Aspects of TGF-beta in Carcinogenesis)

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Stromal Modulators of TGF-β in Cancer

by Brunella Costanza, Ijeoma Adaku Umelo, Justine Bellier, Vincent Castronovo and Andrei Turtoi

J. Clin. Med. 2017, 6(1), 7; https://doi.org/10.3390/jcm6010007 - 06 Jan 2017

Cited by 128 | Viewed by 20806

Abstract

Transforming growth factor-β (TGF-β) is an intriguing cytokine exhibiting dual activities in malignant disease. It is an important mediator of cancer invasion, metastasis and angiogenesis, on the one hand, while it exhibits anti-tumor functions on the other hand. Elucidating the precise role of [...] Read more.

Transforming growth factor-β (TGF-β) is an intriguing cytokine exhibiting dual activities in malignant disease. It is an important mediator of cancer invasion, metastasis and angiogenesis, on the one hand, while it exhibits anti-tumor functions on the other hand. Elucidating the precise role of TGF-β in malignant development and progression requires a better understanding of the molecular mechanisms involved in its tumor suppressor to tumor promoter switch. One important aspect of TGF-β function is its interaction with proteins within the tumor microenvironment. Several stromal proteins have the natural ability to interact and modulate TGF-β function. Understanding the complex interplay between the TGF-β signaling network and these stromal proteins may provide greater insight into the development of novel therapeutic strategies that target the TGF-β axis. The present review highlights our present understanding of how stroma modulates TGF-β activity in human cancers. Full article

(This article belongs to the Special Issue Biological and Clinical Aspects of TGF-beta in Carcinogenesis)

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The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance

by Sunjida Ahmed, Azore-Dee Bradshaw, Shweta Gera, M. Zahidunnabi Dewan and Ruliang Xu

J. Clin. Med. 2017, 6(1), 5; https://doi.org/10.3390/jcm6010005 - 05 Jan 2017

Cited by 125 | Viewed by 13036

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human cancers due to its complicated genomic instability. PDAC frequently presents at an advanced stage with extensive metastasis, which portends a poor prognosis. The known risk factors associated with PDAC include advanced age, [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human cancers due to its complicated genomic instability. PDAC frequently presents at an advanced stage with extensive metastasis, which portends a poor prognosis. The known risk factors associated with PDAC include advanced age, smoking, long-standing chronic pancreatitis, obesity, and diabetes. Its association with genomic and somatic mutations is the most important factor for its aggressiveness. The most common gene mutations associated with PDAC include KRas2, p16, TP53, and Smad4. Among these, Smad4 mutation is relatively specific and its inactivation is found in more than 50% of invasive pancreatic adenocarcinomas. Smad4 is a member of the Smad family of signal transducers and acts as a central mediator of transforming growth factor beta (TGF-β) signaling pathways. The TGF-β signaling pathway promotes many physiological processes, including cell growth, differentiation, proliferation, fibrosis, and scar formation. It also plays a major role in the development of tumors through induction of angiogenesis and immune suppression. In this review, we will discuss the molecular mechanism of TGF-β/Smad4 signaling in the pathogenesis of pancreatic adenocarcinoma and its clinical implication, particularly potential as a prognostic factor and a therapeutic target. Full article

(This article belongs to the Special Issue Biological and Clinical Aspects of TGF-beta in Carcinogenesis)

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Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer

by David Witte, Franziska Zeeh, Thomas Gädeken, Frank Gieseler, Bernhard H. Rauch, Utz Settmacher, Roland Kaufmann, Hendrik Lehnert and Hendrik Ungefroren

J. Clin. Med. 2016, 5(12), 111; https://doi.org/10.3390/jcm5120111 - 30 Nov 2016

Cited by 12 | Viewed by 7215

Abstract

TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages. The final outcome of the TGF-β response is determined by cell-autonomous [...] Read more.

TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages. The final outcome of the TGF-β response is determined by cell-autonomous mechanisms and genetic alterations such as genomic instability and somatic mutations, but also by a plethora of external signals derived from the tumor microenvironment, such as cell-to-cell interactions, growth factors and extracellular matrix proteins and proteolytic enzymes. Serine proteinases mediate their cellular effects via activation of proteinase-activated receptors (PARs), a subclass of G protein-coupled receptors that are activated by proteolytic cleavage. We have recently identified PAR2 as a factor required for TGF-β1-dependent cell motility in ductal pancreatic adenocarcinoma (PDAC) cells. In this article, we review what is known on the TGF-β-PAR2 signaling crosstalk and its relevance for tumor growth and metastasis. Since PAR2 is activated through various serine proteinases, it may couple TGF-β signaling to a diverse range of other physiological processes, such as local inflammation, systemic coagulation or pathogen infection. Moreover, since PAR2 controls expression of the TGF-β type I receptor ALK5, PAR2 may also impact signaling by other TGF-β superfamily members that signal through ALK5, such as myostatin and GDF15/MIC-1. If so, PAR2 could represent a molecular linker between PDAC development and cancer-related cachexia. Full article

(This article belongs to the Special Issue Biological and Clinical Aspects of TGF-beta in Carcinogenesis)

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Switching Roles of TGF-β in Cancer Development: Implications for Therapeutic Target and Biomarker Studies

by Nan Sun, Ayumu Taguchi and Samir Hanash

J. Clin. Med. 2016, 5(12), 109; https://doi.org/10.3390/jcm5120109 - 30 Nov 2016

Cited by 26 | Viewed by 5081

Abstract

TGF-β induces complicated and even opposite responses in numerous biological processes, e.g., tumor suppression in pre-malignant cells and metastasis promotion in cancer cells. However, the cellular contextual determinants of these different TGF-β roles remain elusive, and the driver genes triggering the determinants’ changes [...] Read more.

TGF-β induces complicated and even opposite responses in numerous biological processes, e.g., tumor suppression in pre-malignant cells and metastasis promotion in cancer cells. However, the cellular contextual determinants of these different TGF-β roles remain elusive, and the driver genes triggering the determinants’ changes have not been identified. Recently, however, several findings have provided new insights on the contextual determinants of Smads in TGF-β’s biological processes. These novel switches and their effectors may serve as prognostic biomarkers and therapeutic targets of TGF-β-mediated cancer progression. Full article

(This article belongs to the Special Issue Biological and Clinical Aspects of TGF-beta in Carcinogenesis)

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TGF-β Signaling in Bone Remodeling and Osteosarcoma Progression

by Audrey Lamora, Julie Talbot, Mathilde Mullard, Benedicte Brounais-Le Royer, Françoise Redini and Franck Verrecchia

J. Clin. Med. 2016, 5(11), 96; https://doi.org/10.3390/jcm5110096 - 03 Nov 2016

Cited by 98 | Viewed by 9163

Abstract

Osteosarcomas are the most prevalent malignant primary bone tumors in children. Despite intensive efforts to improve both chemotherapeutics and surgical management, 40% of all osteosarcoma patients succumb to the disease. Specifically, the clinical outcome for metastatic osteosarcoma remains poor; less than 30% of [...] Read more.

Osteosarcomas are the most prevalent malignant primary bone tumors in children. Despite intensive efforts to improve both chemotherapeutics and surgical management, 40% of all osteosarcoma patients succumb to the disease. Specifically, the clinical outcome for metastatic osteosarcoma remains poor; less than 30% of patients who present metastases will survive five years after initial diagnosis. Treating metastatic osteosarcoma thus remains a challenge. One of the main characteristics of osteosarcomas is their ability to deregulate bone remodelling. The invasion of bone tissue by tumor cells indeed affects the balance between bone resorption and bone formation. This deregulation induces the release of cytokines or growth factors initially trapped in the bone matrix, such as transforming growth factor-β (TGF-β), which in turn promote tumor progression. Over the past years, there has been considerable interest in the TGF-β pathway within the cancer research community. This review discusses the involvement of the TGF-β signalling pathway in osteosarcoma development and in their metastatic progression. Full article

(This article belongs to the Special Issue Biological and Clinical Aspects of TGF-beta in Carcinogenesis)

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Dysregulation of TGFβ1 Activity in Cancer and Its Influence on the Quality of Anti-Tumor Immunity

by Kristian M. Hargadon

J. Clin. Med. 2016, 5(9), 76; https://doi.org/10.3390/jcm5090076 - 31 Aug 2016

Cited by 38 | Viewed by 7876

Abstract

TGFβ1 is a pleiotropic cytokine that exhibits a variety of physiologic and immune regulatory functions. Although its influence on multiple cell types is critical for the regulation of numerous biologic processes in the host, dysregulation of both TGFβ1 expression and activity is frequently [...] Read more.

TGFβ1 is a pleiotropic cytokine that exhibits a variety of physiologic and immune regulatory functions. Although its influence on multiple cell types is critical for the regulation of numerous biologic processes in the host, dysregulation of both TGFβ1 expression and activity is frequently observed in cancer and contributes to various aspects of cancer progression. This review focuses on TGFβ1’s contribution to tumor immune suppression and escape, with emphasis on the influence of this regulatory cytokine on the differentiation and function of dendritic cells and T cells. Clinical trials targeting TGFβ1 in cancer patients are also reviewed, and strategies for future therapeutic interventions that build on our current understanding of immune regulation by TGFβ1 are discussed. Full article

(This article belongs to the Special Issue Biological and Clinical Aspects of TGF-beta in Carcinogenesis)

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Mechanisms of TGFβ-Induced Epithelial–Mesenchymal Transition

by Aristidis Moustakas and Carl-Henrik Heldin

J. Clin. Med. 2016, 5(7), 63; https://doi.org/10.3390/jcm5070063 - 29 Jun 2016

Cited by 195 | Viewed by 15654

Abstract

Transitory phenotypic changes such as the epithelial–mesenchymal transition (EMT) help embryonic cells to generate migratory descendants that populate new sites and establish the distinct tissues in the developing embryo. The mesenchymal descendants of diverse epithelia also participate in the wound healing response of [...] Read more.

Transitory phenotypic changes such as the epithelial–mesenchymal transition (EMT) help embryonic cells to generate migratory descendants that populate new sites and establish the distinct tissues in the developing embryo. The mesenchymal descendants of diverse epithelia also participate in the wound healing response of adult tissues, and facilitate the progression of cancer. EMT can be induced by several extracellular cues in the microenvironment of a given epithelial tissue. One such cue, transforming growth factor β (TGFβ), prominently induces EMT via a group of specific transcription factors. The potency of TGFβ is partly based on its ability to perform two parallel molecular functions, i.e. to induce the expression of growth factors, cytokines and chemokines, which sequentially and in a complementary manner help to establish and maintain the EMT, and to mediate signaling crosstalk with other developmental signaling pathways, thus promoting changes in cell differentiation. The molecules that are activated by TGFβ signaling or act as cooperating partners of this pathway are impossible to exhaust within a single coherent and contemporary report. Here, we present selected examples to illustrate the key principles of the circuits that control EMT under the influence of TGFβ. Full article

(This article belongs to the Special Issue Biological and Clinical Aspects of TGF-beta in Carcinogenesis)

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