Targeting Growth Factor Signaling Pathways in Pancreatic Cancer: Towards Inhibiting Chemoresistance

Xelwa, Ntombikayise; Candy, Geoffrey P.; Devar, John; Omoshoro-Jones, J.; Nweke, Ekene Emmanuel

doi:10.3389/fonc.2021.683788

Cited by 14 publications

(8 citation statements)

References 130 publications

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“…In particular, VEGF acts as a mitogen for endothelial cells. Its overexpression in pancreatic cancer is associated with angiogenesis, increased tumor size, and reduced patient survival [69,71]. As mentioned earlier, PDAC is often characterized by significant fibrosis and dysregulated TGF-β signaling [72,73].…”

Section: Gene and Protein Expression Analysis Of 3d Bioprinting Pancr...mentioning

confidence: 94%

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Gelatin methacryloyl and Laponite bioink for 3D bioprinted organotypic tumor modeling

et al. 2023

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Three-dimensional (3D) in vitro tumor models that can capture the pathophysiology of human tumors are essential for cancer biology and drug development. However, simulating the tumor microenvironment is still challenging because it consists of a heterogeneous mixture of various cellular components and biological factors. In this regard, current extracellular matrix (ECM)-mimicking hydrogels used in tumor tissue engineering lack physical interactions that can keep biological factors released by encapsulated cells within the hydrogel and improve paracrine interactions. Here, we developed a nanoengineered ion-covalent cross-linkable bioink to construct 3D bioprinted organotypic tumor models. The bioink was designed to implement the tumor ECM by creating an interpenetrating network composed of gelatin methacryloyl (GelMA), a light cross-linkable polymer, and synthetic nanosilicate (Laponite) that exhibits a unique ionic charge to improve retention of biological factors released by the encapsulated cells and assist in paracrine signals. The physical properties related to printability were evaluated to analyze the effect of Laponite hydrogel on bioink. Low GelMA (5%) with high Laponite (2.5-3.5%) composite hydrogels and high GelMA (10%) with low Laponite (1.0-2.0%) composite hydrogels showed acceptable mechanical properties for 3D printing. However, a low GelMA composite hydrogel with a high Laponite content could not provide acceptable cell viability. Fluorescent cell labeling studies showed that as the proportion of Laponite increased, the cells became more aggregated to form larger 3D tumor structures. RT-qPCR and western blot experiments showed that an increase in the Laponite ratio induces upregulation of growth factor and tissue remodeling-related genes and proteins in tumor cells. In contrast, cell cycle and proliferation-related genes were downregulated. On the other hand, concerning fibroblasts, the increase in the Laponite ratio indicated an overall upregulation of the mesenchymal phenotype-related genes and proteins. Our study may provide a rationale for using Laponite-based hydrogels in 3D cancer modeling.

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Section: Gene and Protein Expression Analysis Of 3d Bioprinting Pancr...mentioning

confidence: 94%

“…Growth factors such as VEGF, PDGF-β receptor, and IGF1 have been shown to affect cancer cell survival, progression, and chemoresistance in various types of cancer, including pancreatic cancer [69,70]. In particular, VEGF acts as a mitogen for endothelial cells.…”

Section: Gene and Protein Expression Analysis Of 3d Bioprinting Pancr...mentioning

confidence: 99%

Gelatin methacryloyl and Laponite bioink for 3D bioprinted organotypic tumor modeling

et al. 2023

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“…Growth factors play essential roles in PC cell survival, progression, and drug resistance[ 130 ]. For example, TGF-β contributes to PDAC progression by inducing N-glycomic changes in SMA-related and MAD-related protein 4-deficient PDAC cell line PaTu-8955S cells[ 131 ].…”

Section: Treatment Optionsmentioning

confidence: 99%

Clinical diagnosis and management of pancreatic cancer: Markers, molecular mechanisms, and treatment options

Zhang¹,

Liu²,

Yang³

2022

World J Gastroenterol

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Pancreatic cancer (PC) is the third-leading cause of cancer deaths. The overall 5-year survival rate of PC is 9%, and this rate for metastatic PC is below 3%. However, the PC-induced death cases will increase about 2-fold by 2060. Many factors such as genetic and environmental factors and metabolic diseases can drive PC development and progression. The most common type of PC in the clinic is pancreatic ductal adenocarcinoma, comprising approximately 90% of PC cases. Multiple pathogenic processes including but not limited to inflammation, fibrosis, angiogenesis, epithelial-mesenchymal transition, and proliferation of cancer stem cells are involved in the initiation and progression of PC. Early diagnosis is essential for curable therapy, for which a combined panel of serum markers is very helpful. Although some mono or combined therapies have been approved by the United States Food and Drug Administration for PC treatment, current therapies have not shown promising outcomes. Fortunately, the development of novel immunotherapies, such as oncolytic viruses-mediated treatments and chimeric antigen receptor-T cells, combined with therapies such as neoadjuvant therapy plus surgery, and advanced delivery systems of immunotherapy will improve therapeutic outcomes and combat drug resistance in PC patients. Herein, the pathogenesis, molecular signaling pathways, diagnostic markers, prognosis, and potential treatments in completed, ongoing, and recruiting clinical trials for PC were reviewed.

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“…Advanced HCC is resistant to both chemotherapy and radiotherapy [ 13 ]. Similarly, pancreatic cancer also develops chemoresistance, which hinders the effectiveness of the treatment, imparting poor response and quick relapse [ 14 ]. These findings urge the need to develop novel chemotherapeutic agents of greater potency and selectivity with no resistance from the targeted cancerous cells.…”

Section: Introductionmentioning

confidence: 99%

1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking

Elsawi,

Shahin,

Elbendary

et al. 2024

Pharmaceuticals

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Targeting the VEGFR-2 signaling pathway is an inveterate approach toward combating pancreatic and hepatocellular cancers. Based on Sunitinib, the FDA-approved VEGFR-2 inhibitor, novel indolin-2-one-triazole hybrids were designed and synthesized as anti-hepatocellular and anti-pancreatic cancer agents with VEGFR-2 inhibitory activity. All the targeted compounds were assessed for their anti-cancer activity, revealing IC50 values extending from 0.17 to 4.29 µM for PANC1 and 0.58 to 4.49 µM for HepG2 cell lines. An extensive SAR study was conducted to explore the effect of different substituents along with N-alkylation. The potent anti-cancer analogs 11d, 11e, 11g, 11k and 14c were evaluated for their VEGFR-2 inhibitory actions, where their IC50 values ranged from 16.3 to 119.6 nM compared to Sorafenib, which revealed an IC50 of 29.7 nM, having compound 11d as the most active analog. An in silico ADME study was performed to confirm the drug-likeness of the synthesized compounds. Finally, molecular docking simulation was conducted for the most potent VEGFR-2 inhibitor (11d), demonstrating the strong binding with the vital amino acid residues of the VEGFR-2 ATP binding site.

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Targeting Growth Factor Signaling Pathways in Pancreatic Cancer: Towards Inhibiting Chemoresistance

Cited by 14 publications

References 130 publications

Gelatin methacryloyl and Laponite bioink for 3D bioprinted organotypic tumor modeling

Gelatin methacryloyl and Laponite bioink for 3D bioprinted organotypic tumor modeling

Clinical diagnosis and management of pancreatic cancer: Markers, molecular mechanisms, and treatment options

1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking

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