scholarly journals Decoding the Roles of Astrocytes and Hedgehog Signaling in Medulloblastoma

2021 ◽  
Author(s):  
Terence Teixeira Duarte ◽  
Silvia Teixeira ◽  
Luis Gonzalez-Reyes ◽  
Rui Manuel Reis
Keyword(s):  
Tumor Microenvironment ◽  
Sonic Hedgehog ◽  
Stromal Cells ◽  
Hedgehog Signaling ◽  
Prognostic Markers ◽  
Therapeutic Strategies ◽  
Molecular Networks ◽  
Molecular Subgroup ◽  
Transduction Mechanisms ◽  
Tumoral Cells

The molecular evolution of medulloblastoma is more complex than was previously imagined as emerging evidence suggests that multiples interactions between the tumor cells and components of the tumor microenvironment (TME) are important for tumor promotion and progression. The identification of several molecular networks within the TME, which interact with tumoral cells, has provided new clues to understand the tumorigenic roles of many TME components as well as potential therapeutic targets. In this review, we discuss the most recent studies regarding the roles of astrocytes in supporting the sonic hedgehog (SHH)–activated medulloblastoma molecular subgroup, and provide an overview of medulloblastoma progression through SHH expression and signal transduction mechanisms into the complex tumor microenvironment. In addition, we highlight the associations between tumor and stromal cells as possible prognostic markers and new therapeutic strategies.

scholarly journals Decoding the Roles of Astrocytes and Hedgehog Signaling in Medulloblastoma

2021 ◽  
Vol 28 (4) ◽  
pp. 3058-3070
Author(s):  
Terence Teixeira Duarte ◽  
Silvia Aparecida Teixeira ◽  
Luis Gonzalez-Reyes ◽  
Rui Manuel Reis
Keyword(s):  
Tumor Microenvironment ◽  
Sonic Hedgehog ◽  
Stromal Cells ◽  
Hedgehog Signaling ◽  
Prognostic Markers ◽  
Therapeutic Strategies ◽  
Molecular Networks ◽  
Transduction Mechanisms ◽  
Tumoral Cells ◽  
Multiple Interactions

The molecular evolution of medulloblastoma is more complex than previously imagined, as emerging evidence suggests that multiple interactions between the tumor cells and components of the tumor microenvironment (TME) are important for tumor promotion and progression. The identification of several molecular networks within the TME, which interact with tumoral cells, has provided new clues to understand the tumorigenic roles of many TME components as well as potential therapeutic targets. In this review, we discuss the most recent studies regarding the roles of astrocytes in supporting sonic hedgehog (SHH) subgroup medulloblastoma (MB) and provide an overview of MB progression through SHH expression and signal transduction mechanisms into the complex tumor microenvironment. In addition, we highlight the associations between tumor and stromal cells as possible prognostic markers that could be targeted with new therapeutic strategies.

scholarly journals KCTD15 inhibits the Hedgehog pathway in Medulloblastoma cells by increasing protein levels of the oncosuppressor KCASH2

Oncogenesis ◽  
2019 ◽  
Vol 8 (11) ◽  
Author(s):  
Eleonora Spiombi ◽  
Annapaola Angrisani ◽  
Simone Fonte ◽  
Giuseppina De Feudis ◽  
Francesca Fabretti ◽  
...  
Keyword(s):  
Complex Network ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Adult Life ◽  
Molecular Subgroup ◽  
Protein Levels ◽  
Proteomic Approach ◽  
Tetramerization Domain ◽  
Development And Differentiation ◽  
Physiologic Role

Abstract Medulloblastoma (MB) is the most common malignant childhood brain tumor. About 30% of all MBs belong to the I molecular subgroup, characterized by constitutive activation of the Sonic Hedgehog (Hh) pathway. The Hh pathway is involved in several fundamental processes during embryogenesis and in adult life and its deregulation may lead to cerebellar tumorigenesis. Indeed, Hh activity must be maintained via a complex network of activating and repressor signals. One of these repressor signals is KCASH2, belonging to the KCASH family of protein, which acts as negative regulators of the Hedgehog signaling pathway during cerebellar development and differentiation. KCASH2 leads HDAC1 to degradation, allowing hyperacetylation and inhibition of transcriptional activity of Gli1, the main effector of the Hh pathway. In turn, the KCASH2 loss leads to persistent Hh activity and eventually tumorigenesis. In order to better characterize the physiologic role and modulation mechanisms of KCASH2, we have searched through a proteomic approach for new KCASH2 interactors, identifying Potassium Channel Tetramerization Domain Containing 15 (KCTD15). KCTD15 is able to directly interact with KCASH2, through its BTB/POZ domain. This interaction leads to increase KCASH2 stability which implies a reduction of the Hh pathway activity and a reduction of Hh-dependent MB cells proliferation. Here we report the identification of KCTD15 as a novel player in the complex network of regulatory proteins, which modulate Hh pathway, this could be a promising new target for therapeutic approach against MB.

SONIC HEDGEHOG SIGNALING IN HUMAN PROSTATE AND BONE STROMAL CELLS: POTENTIAL ROLES IN LOCALIZED AND DISSEMINATED HUMAN PROSTATE CANCER GROWTH

2008 ◽  
Vol 179 (4S) ◽  
pp. 394-395
Author(s):  
Katsumi Shigemura ◽  
Haiyen E Zhau ◽  
Goudong Zhu ◽  
Masato Fujisawa ◽  
Akinobu Gotoh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Sonic Hedgehog ◽  
Stromal Cells ◽  
Hedgehog Signaling ◽  
Human Prostate ◽  
Cancer Growth ◽  
Human Prostate Cancer ◽  
Sonic Hedgehog Signaling

scholarly journals Targeting Tumor Microenvironment for Cancer Therapy

2019 ◽  
Vol 20 (4) ◽  
pp. 840 ◽  
Author(s):  
Catarina Roma-Rodrigues ◽  
Rita Mendes ◽  
Pedro Baptista ◽  
Alexandra Fernandes
Keyword(s):  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Tumor Tissue ◽  
Physiological State ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
Cancer Therapies ◽  
Multicellular Tumor Spheroids ◽  
Common Features ◽  
Anti Cancer

Cancer development is highly associated to the physiological state of the tumor microenvironment (TME). Despite the existing heterogeneity of tumors from the same or from different anatomical locations, common features can be found in the TME maturation of epithelial-derived tumors. Genetic alterations in tumor cells result in hyperplasia, uncontrolled growth, resistance to apoptosis, and metabolic shift towards anaerobic glycolysis (Warburg effect). These events create hypoxia, oxidative stress and acidosis within the TME triggering an adjustment of the extracellular matrix (ECM), a response from neighbor stromal cells (e.g., fibroblasts) and immune cells (lymphocytes and macrophages), inducing angiogenesis and, ultimately, resulting in metastasis. Exosomes secreted by TME cells are central players in all these events. The TME profile is preponderant on prognosis and impacts efficacy of anti-cancer therapies. Hence, a big effort has been made to develop new therapeutic strategies towards a more efficient targeting of TME. These efforts focus on: (i) therapeutic strategies targeting TME components, extending from conventional therapeutics, to combined therapies and nanomedicines; and (ii) the development of models that accurately resemble the TME for bench investigations, including tumor-tissue explants, “tumor on a chip” or multicellular tumor-spheroids.

scholarly journals Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments

2020 ◽  
Vol 21 (3) ◽  
pp. 758 ◽  
Author(s):  
Kuo-Shyang Jeng ◽  
Chiung-Fang Chang ◽  
Shu-Sheng Lin
Keyword(s):  
Tumor Microenvironment ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Cancer Progression ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Tumor Development ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Tumor Microenvironments

During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.

scholarly journals How Cells Communicate with Each Other in the Tumor Microenvironment: Suggestions to Design Novel Therapeutic Strategies in Cancer Disease

2021 ◽  
Vol 22 (5) ◽  
pp. 2550
Author(s):  
Roberto Zefferino ◽  
Claudia Piccoli ◽  
Sante Di Gioia ◽  
Nazzareno Capitanio ◽  
Massimo Conese
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Stromal Cells ◽  
Therapeutic Strategies ◽  
Invasion And Metastasis ◽  
Complex Interplay ◽  
Cancer Disease ◽  
Novel Therapeutic Strategies ◽  
Early Late ◽  
Novel Therapeutic

Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with cancer, it is not correct to omit the immune system, as well as neglecting its role in resisting or succumbing to formation and progression of incipient neoplasia until the formation of micrometastasis, nevertheless what really occurs in the tumor microenvironment (TME), which are the main players and which are the tumor or body allies, is still unclear. The goal of this article is to discuss how the pivotal players act, which can enhance or contrast cancer progression during two important process: “Activating Invasion and Metastasis” and the “Avoiding Immune Destruction”, with a particular emphasis on the interplay among GJIC, Panx-HCs, and the purinergic system in the TME without disregarding the inflammasome and cytokines thereof derived. In particular, the complex and contrasting roles of Panx1/P2X7R signalosome in tumor facilitation and/or inhibition is discussed in regard to the early/late phases of the carcinogenesis. Finally, considering this complex interplay in the TME between cancer cells, stromal cells, immune cells, and focusing on their means of communication, we should be capable of revealing harmful messages that help the cancer growth and transform them in body allies, thus designing novel therapeutic strategies to fight cancer in a personalized manner.

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