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Chai JY, Sugumar V, Alshawsh MA, Wong WF, Arya A, Chong PP, Looi CY. The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis. Biomedicines 2021; 9:1188. [PMID: 34572373 PMCID: PMC8466551 DOI: 10.3390/biomedicines9091188] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/29/2021] [Accepted: 09/01/2021] [Indexed: 12/22/2022] Open
Abstract
The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.
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Affiliation(s)
- Jian Yi Chai
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
| | - Vaisnevee Sugumar
- School of Medicine, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia;
| | | | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;
| | - Aditya Arya
- School of Biosciences, Faculty of Science, Building 184, The University of Melbourne, Melbourne, VIC 3010, Australia;
| | - Pei Pei Chong
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia
| | - Chung Yeng Looi
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia
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Polani F, Grierson PM, Lim KH. Stroma-targeting strategies in pancreatic cancer: Past lessons, challenges and prospects. World J Gastroenterol 2021; 27:2105-2121. [PMID: 34025067 PMCID: PMC8117738 DOI: 10.3748/wjg.v27.i18.2105] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/09/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to emerge as the second leading cause of cancer-related death after 2030. Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC. To date, combination chemotherapy remains the mainstay of treatment for most PDAC patients. Compared to other cancer types, treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorter-lived. Aside from typically harboring genetic alterations that to date remain un-druggable and are drivers of treatment resistance, PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance. However, emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes. These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression. The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells, stromal fibroblasts, and immune cells. This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease. Here, we provide a concise review on lessons learned from past stroma-targeting strategies, new challenges revealed from recent preclinical and clinical studies, as well as new prospects in the treatment of PDAC.
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Affiliation(s)
- Faran Polani
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, United States
| | - Patrick M Grierson
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, United States
| | - Kian-Huat Lim
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, United States
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Martins Cavaco AC, Dâmaso S, Casimiro S, Costa L. Collagen biology making inroads into prognosis and treatment of cancer progression and metastasis. Cancer Metastasis Rev 2021; 39:603-623. [PMID: 32447477 DOI: 10.1007/s10555-020-09888-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Progression through dissemination to tumor-surrounding tissues and metastasis development is a hallmark of cancer that requires continuous cell-to-cell interactions and tissue remodeling. In fact, metastization can be regarded as a tissue disease orchestrated by cancer cells, leading to neoplastic colonization of new organs. Collagen is a major component of the extracellular matrix (ECM), and increasing evidence suggests that it has an important role in cancer progression and metastasis. Desmoplasia and collagen biomarkers have been associated with relapse and death in cancer patients. Despite the increasing interest in ECM and in the desmoplastic process in tumor microenvironment as prognostic factors and therapeutic targets in cancer, further research is required for a better understanding of these aspects of cancer biology. In this review, published evidence correlating collagen with cancer prognosis is retrieved and analyzed, and the role of collagen and its fragments in cancer pathophysiology is discussed.
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Affiliation(s)
- Ana C Martins Cavaco
- Luis Costa Lab, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, 1649-028, Lisboa, Portugal
| | - Sara Dâmaso
- Serviço de Oncologia, Hospital de Santa Maria-CHULN, 1649-028, Lisboa, Portugal
| | - Sandra Casimiro
- Luis Costa Lab, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, 1649-028, Lisboa, Portugal
| | - Luís Costa
- Luis Costa Lab, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, 1649-028, Lisboa, Portugal.
- Serviço de Oncologia, Hospital de Santa Maria-CHULN, 1649-028, Lisboa, Portugal.
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van Mackelenbergh MG, Stroes CI, Spijker R, van Eijck CHJ, Wilmink JW, Bijlsma MF, van Laarhoven HWM. Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 11:E588. [PMID: 31035512 PMCID: PMC6562438 DOI: 10.3390/cancers11050588] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/19/2019] [Accepted: 04/22/2019] [Indexed: 12/14/2022] Open
Abstract
The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90-1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA)high tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26-1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients.
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Affiliation(s)
- Madelaine G van Mackelenbergh
- Laboratory of Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Charlotte I Stroes
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - René Spijker
- Medical Library, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
- Cochrane Netherlands, Julius Center, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
| | - Casper H J van Eijck
- Department of Surgery, Erasmus MC, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands.
| | - Johanna W Wilmink
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Maarten F Bijlsma
- Laboratory of Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
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