Targeting the Complement Pathway in Malignant Glioma Microenvironments

Zhu, Hongtao; Yu, Xingjiang; Zhang, Suojun; Shu, Kai

doi:10.3389/fcell.2021.657472

Cited by 17 publications

(13 citation statements)

References 135 publications

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“…Complement proteins were shown to be overexpressed in several common human malignancies ( 121 ), and their expression are linked with clinical outcomes ( 29 ). Predictably, prognostic significance of complement gene expression is dependent on malignancy type.…”

Section: Complement Utility As Biomarkermentioning

confidence: 99%

Inside-Out of Complement in Cancer

et al. 2022

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The role of complement in cancer has received increasing attention over the last decade. Recent studies provide compelling evidence that complement accelerates cancer progression. Despite the pivotal role of complement in fighting microbes, complement seems to suppress antitumor immunity via regulation of host cell in the tumor microenvironment. Although most studies link complement in cancer to complement activation in the extracellular space, the discovery of intracellular activation of complement, raises the question: what is the relevance of this process for malignancy? Intracellular activation is pivotal for the survival of immune cells. Therefore, complement can be important for tumor cell survival and growth regardless of the role in immunosuppression. On the other hand, because intracellular complement (the complosome) is indispensable for activation of T cells, these functions will be essential for priming antitumor T cell responses. Here, we review functions of complement in cancer with the consideration of extra and intracellular pathways of complement activation and spatial distribution of complement proteins in tumors and periphery and provide our take on potential significance of complement as biomarker and target for cancer therapy.

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Section: Complement Utility As Biomarkermentioning

confidence: 99%

Inside-Out of Complement in Cancer

et al. 2022

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“…Secondly, upregulated cell pathways can be targeted [ 83 , 84 , 85 ], for example, using miRNAs that disrupt those pathways [ 86 , 87 ]. Similarly, the tumour microenvironment can be a site of therapeutic interest [ 88 , 89 , 90 , 91 , 92 ]: one example is exploiting the high concentration of Reactive Oxygen Species (ROS) with ROS-sensitive NMeds that would release the drug only in the presence of ROS [ 93 , 94 ]. However, major limitations to these strategies lay in the poor stability of sensitive molecules, such as RNAs and the lack of cell specificity that could still lead to off-target effects.…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma Multiforme Selective Nanomedicines for Improved Anti-Cancer Treatments

et al. 2022

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Glioblastoma Multiforme (GBM) is a devastating disease with a low survival rate and few efficacious treatment options. The fast growth, late diagnostics, and off-target toxicity of currently used drugs represent major barriers that need to be overcome to provide a viable cure. Nanomedicines (NMeds) offer a way to overcome these pitfalls by protecting and loading drugs, increasing blood half-life, and being targetable with specific ligands on their surface. In this study, the FDA-approved polymer poly (lactic-co-glycolic) acid was used to optimise NMeds that were surface modified with a series of potential GBM-specific ligands. The NMeds were fully characterised for their physical and chemical properties, and then in vitro testing was performed to evaluate cell uptake and GBM cell specificity. While all targeted NMeds showed improved uptake, only those decorated with the-cell surface vimentin antibody M08 showed specificity for GBM over healthy cells. Finally, the most promising targeted NMed candidate was loaded with the well-known chemotherapeutic, paclitaxel, to confirm targeting and therapeutic effects in C6 GBM cells. These results demonstrate the importance of using well-optimised NMeds targeted with novel ligands to advance delivery and pharmaceutical effects against diseased cells while minimising the risk for nearby healthy cells.

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“…It was shown that C3a or C5a, which are both anaphylatoxins, can cause inflammation in a variety of ways by releasing histamine, activating other leukocytes, and stimulating the production of inflammatory mediators like TNF-alpha, IL-6, IL-1β, and IL-1 [ 13 ] . It has been shown that these anaphylatoxins generated during tumor-associated complement activation can reshape the tumor microenvironment and play a role in tumor cell proliferation, resistance to chemotherapy, and angiogenesis within pancreatic cancer [ 14 ] . C5a has been shown to upregulate angiogenic factors such as vascular endothelial growth factor (VEGF) in cancer cells which plays a huge role in the development of newly formed blood vessels allowing the tumor to grow.…”

Section: Introductionmentioning

confidence: 99%

Targeting the complement system in pancreatic cancer drug resistance: a novel therapeutic approach

Hussain¹,

Das²,

Pramanik³

et al. 2022

Cancer Drug Resist

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Pancreatic cancer is ranked as the fourth leading cause of cancer-related mortality and is predicted to become the second leading cause of cancer-related death by 2030. The cause of this high mortality rate is due to pancreatic ductal adenocarcinoma’s rapid progression and metastasis, and development of drug resistance. Today, cancer immunotherapy is becoming a strong candidate to not only treat various cancers but also to combat against chemoresistance. Studies have suggested that complement system pathways play an important role in cancer progression and chemoresistance, especially in pancreatic cancer. A recent report also suggested that several signaling pathways play an important role in causing chemoresistance in pancreatic cancer, major ones including nuclear factor kappa B, signal transducer and activator of transcription 3, c-mesenchymal-epithelial transition factor, and phosphoinositide-3-kinase/protein kinase B. In addition, it has also been proven that the complement system has a very active role in establishing the tumor microenvironment, which would aid in promoting tumorigenesis, progression, metastasis, and recurrence. Interestingly, it has been shown that the downstream products of the complement system directly upregulate inflammatory mediators, which in turn activate these chemo-resistant pathways. Therefore, targeting complement pathways could be an innovative approach to combat against pancreatic cancer drugs resistance. In this review, we have discussed the role of complement system pathways in pancreatic cancer drug resistance and a special focus on the complement as a therapeutic target in pancreatic cancer.

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Targeting the Complement Pathway in Malignant Glioma Microenvironments

Cited by 17 publications

References 135 publications

Inside-Out of Complement in Cancer

Inside-Out of Complement in Cancer

Glioblastoma Multiforme Selective Nanomedicines for Improved Anti-Cancer Treatments

Targeting the complement system in pancreatic cancer drug resistance: a novel therapeutic approach

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