Cancer-Associated Fibroblasts: Master Tumor Microenvironment Modifiers

Wright, Kellen D.; Ly, Thuc; Kriet, Matthew; Czirók, András; Thomas, Sufi M.

doi:10.3390/cancers15061899

Cited by 53 publications

(17 citation statements)

References 110 publications

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“…The tumor microenvironment, which includes cancer-associated fibroblasts, endothelial cells, and tumor-associated immune cells, plays a significant role in the initiation, progression, and migration of tumor cells 32 . In the previous section, we showed that our advanced tumoroid-on-a-plate in vitro model can incorporate customized ECM for relevant cancer progression assays.…”

Section: Resultsmentioning

confidence: 99%

Tumoroid-on-a-Plate (ToP): Physiologically Relevant Cancer Model Generation and Therapeutic Screening

Seyfoori,

Liu,

Caruncho

et al. 2024

Preprint

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Employing three-dimensional (3D) in vitro models, including tumor organoids and spheroids, stands pivotal in enhancing cancer therapy. These models bridge the gap between 2D cell cultures and complex in vivo environments, effectively mimicking the intricate cellular interplay and microenvironmental factors found in solid tumors. Consequently, they offer versatile tools for comprehensive studies into cancer progression, drug responses, and tailored therapies. In this study, we present a novel open-surface microfluidic-integrated platform called the Tumoroid-on-a-Plate (ToP) device, designed for generating intricate predictive 3D solid tumor models. By incorporating a tumor mass, stromal cells, and extracellular matrix components, we successfully replicate the complexity of glioblastoma (GBM) and pancreatic adenocarcinoma (PDAC) within our system. Using our advanced ToP model, we were able to successfully screen the effect of various GBM extracellular matrix compositions, such as Collagen and Reelin, on the invasiveness of the GBM cells with the ToP model. The ToP in vitro model also allowed for the screening of chemotherapeutic drugs such as temozolomide and iron-chelators in a single and binary treatment setting on the complex ECM-embedded tumoroids. This helped to investigate the toxic effect of different therapeutics on the viability and apoptosis of our in vitro GBM and PDAC cancer models. Additionally, by co-culturing human-derived fibroblast cells with PDAC tumoroids, the pro-invasive impact of the stromal component of the tumor microenvironment on growth behavior and drug response of the tumoroids was revealed. This study underscores the transformative role of predictive 3D models in deciphering cancer intricacies and highlights the promise of ToP in advancing therapeutic understanding.

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Section: Resultsmentioning

confidence: 99%

Tumoroid-on-a-Plate (ToP): Physiologically Relevant Cancer Model Generation and Therapeutic Screening

Seyfoori,

Liu,

Caruncho

et al. 2024

Preprint

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“…CAFs also contribute to the immunosuppressive tumor microenvironment observed in PDAC by secreting cytokines such as interleukin-6 (IL-6) and interleukin-10 (IL-10), which can inhibit the function of immune cells and further facilitate tumor growth and metastasis ( Morgan et al ., 2023 ). CAFs significantly influence the pancreatic cancer progression through their role in ECM remodeling, secretion of growth factors and cytokines, and contribution to an immunosuppressive microenvironment ( Wright et al ., 2023 ). Understanding the intricate signaling networks between CAFs and cancer cells offers promising opportunities for the development of targeted therapies aimed at disrupting these interactions and thereby inhibiting PDAC progression and metastasis ( Fig.…”

Section: Cancer-associated Fibroblasts (Cafs)mentioning

confidence: 99%

Tumor Stroma as a Therapeutic Target for Pancreatic Ductal Adenocarcinoma

Lee,

Han,

Jung

et al. 2024

Biomol Ther (Seoul)

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Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis owing to its desmoplastic stroma. Therefore, therapeutic strategies targeting this tumor stroma should be developed. In this study, we describe the heterogeneity of cancer-associated fibroblasts (CAFs) and their diverse roles in the progression, immune evasion, and resistance to treatment of PDAC. We subclassified the spatial distribution and functional activity of CAFs to highlight their effects on prognosis and drug delivery. Extracellular matrix components such as collagen and hyaluronan are described for their roles in tumor behavior and treatment outcomes, implying their potential as therapeutic targets. We also discussed the roles of extracellular matrix (ECM) including matrix metalloproteinases and tissue inhibitors in PDAC progression. Finally, we explored the role of the adaptive and innate immune systems in shaping the PDAC microenvironment and potential therapeutic strategies, with a focus on immune cell subsets, cytokines, and immunosuppressive mechanisms. These insights provide a comprehensive understanding of PDAC and pave the way for the development of prognostic markers and therapeutic interventions.

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“…They can originate not just from fibroblasts, but many different cell types, such as endothelial cells. 14,15 CAFs affect both the biophysical TME through fibrin deposition and the biochemical TME by secreting factors such as cytokines and growth factors that contribute to cancer plasticity and immune suppression 16–18 ( Fig. 1 ) .…”

Section: The Tumor Microenvironmentmentioning

confidence: 99%

Biophysical and biochemical aspects of immune cell–tumor microenvironment interactions

Benmelech,

Le,

McKay

et al. 2024

APL Bioengineering

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The tumor microenvironment (TME), composed of and influenced by a heterogeneous set of cancer cells and an extracellular matrix, plays a crucial role in cancer progression. The biophysical aspects of the TME (namely, its architecture and mechanics) regulate interactions and spatial distributions of cancer cells and immune cells. In this review, we discuss the factors of the TME—notably, the extracellular matrix, as well as tumor and stromal cells—that contribute to a pro-tumor, immunosuppressive response. We then discuss the ways in which cells of the innate and adaptive immune systems respond to tumors from both biochemical and biophysical perspectives, with increased focus on CD8+ and CD4+ T cells. Building upon this information, we turn to immune-based antitumor interventions—specifically, recent biophysical breakthroughs aimed at improving CAR-T cell therapy.

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Cancer-Associated Fibroblasts: Master Tumor Microenvironment Modifiers

Cited by 53 publications

References 110 publications

Tumoroid-on-a-Plate (ToP): Physiologically Relevant Cancer Model Generation and Therapeutic Screening

Tumoroid-on-a-Plate (ToP): Physiologically Relevant Cancer Model Generation and Therapeutic Screening

Tumor Stroma as a Therapeutic Target for Pancreatic Ductal Adenocarcinoma

Biophysical and biochemical aspects of immune cell–tumor microenvironment interactions

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