Breaking the stromal barrier in pancreatic cancer: Advances and challenges

Chakkera, Mohana; Foote, Jeremy B.; Farran, Batoul; Nagaraju, Ganji Purnachandra

doi:10.1016/j.bbcan.2023.189065

Cited by 3 publications

(2 citation statements)

References 173 publications

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“…The ECM, primarily composed of fibrous proteins, proteoglycans, enzymes, and soluble factors, plays a crucial role in stromal architecture and function. , Collagen, the most abundant fibrous protein, interacts with cancer cell integrin receptors, activating downstream signaling pathways to promote epithelial–mesenchymal transition and tumor cell invasion . Hyaluronic acid, a key proteoglycan, enhances stromal rigidity and interstitial pressure, facilitating tumor progression and metastasis .…”

Section: Composition Of the Interstitial Microenvironment In Pancreat...mentioning

confidence: 99%

Breaking Down Barriers in Drug Delivery by Stromal Remodeling Approaches in Pancreatic Cancer

Zhou,

Ma,

Sheng

et al. 2024

Mol. Pharmaceutics

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Pancreatic cancer remains a formidable challenge in oncology due to its aggressive nature and limited treatment options. The dense stroma surrounding pancreatic tumors not only provides structural support but also presents a formidable barrier to effective therapy, hindering drug penetration and immune cell infiltration. This review delves into the intricate interplay between stromal components and cancer cells, highlighting their impact on treatment resistance and prognosis. Strategies for stromal remodeling, including modulation of cancerassociated fibroblasts (CAFs), pancreatic stellate cells (PSCs) activation states, and targeting extracellular matrix (ECM) components, are examined for their potential to enhance drug penetration and improve therapeutic efficacy. Integration of stromal remodeling with conventional therapies, such as chemotherapy and immunotherapy, is discussed along with the emerging field of intelligent nanosystems for targeted drug delivery. This comprehensive overview underscores the importance of stromal remodeling in pancreatic cancer treatment and offers insights into promising avenues for future research and clinical translation.

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Section: Composition Of the Interstitial Microenvironment In Pancreat...mentioning

confidence: 99%

Breaking Down Barriers in Drug Delivery by Stromal Remodeling Approaches in Pancreatic Cancer

Zhou,

Ma,

Sheng

et al. 2024

Mol. Pharmaceutics

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show abstract

“…As tumors grow, fibrotic tissue develops and locally enter a hypoxic stage caused by limited access to nutrients and oxygen leading to apoptosis and cell death ( 4 ). The tumor-related stroma and extracellular matrix (ECM) reduce drug penetrance and efficacy ( 5 , 6 ). To understand molecular mechanisms in cancer cells, e.g.…”

Section: Introductionmentioning

confidence: 99%

Architectural organization and molecular profiling of 3D cancer heterospheroids and their application in drug testing

Nielsen,

Madsen,

Larsen

et al. 2024

Front. Oncol.

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3D cancer cell cultures have enabled new opportunities for replacing compound testing in experimental animals. However, most solid tumors are composed of multiple cell types, including fibroblasts. In this study we developed multicellular tumor heterospheroids composed of cancer and fibroblasts cell lines. We developed heterospheroids by combining HT-29, MCF-7, PANC-1 or SW480 with 1BR.3.G fibroblasts, which we have previously reported support spheroid formation. We also tested fibroblast cell lines, MRC-5, GM00498 and HIF, but 1BR.3.G was found to best form heterospheroids with morphological similarity to in vivo tumor tissue. The architectural organization of heterospheroids was based on histological examination using immunohistochemistry. We found that HT-29 and MCF-7 cells developed spheroids with the cancer cells surrounding the fibroblasts, whereas PANC-1 cells interspersed with the fibroblasts and SW480 cells were surrounded by fibroblasts. The fibroblasts also expressed collagen-1 and FAP-α, and whole transcriptomic analysis (WTA) showed abundant ECM- and EMT-related expression in heterospheroids, thus reflecting a representative tumor-like microenvironment. The WTA showed that PANC-1 heterospheroids possess a strong EMT profile with abundant Vimentin and CDH2 expression. Drug testing was evaluated by measuring cytotoxicity of 5FU and cisplatin using cell viability and apoptosis assays. We found no major impact on the cytotoxicity when fibroblasts were added to the spheroids. We conclude that the cancer cell lines together with fibroblasts shape the architectural organization of heterospheroids to form tumor-like morphology, and we propose that the various 3D tumor structures can be used for drug testing directed against the cancer cells as well as the fibroblasts.

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The BRD4 Inhibitor I-BET-762 Reduces HO-1 Expression in Macrophages and the Pancreas of Mice

Leal,

Liby

2024

IJMS

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In pancreatic cancer, the tumor microenvironment (TME) accounts for up to 90% of the tumor mass. Pancreatitis, characterized by the increased infiltration of macrophages into the pancreas, is a known risk factor for pancreatic cancer. The NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor regulates responses to oxidative stress and can promote cancer and chemoresistance. NRF2 also attenuates inflammation through the regulation of macrophage-specific genes. Heme oxygenase 1 (HO-1) is expressed by anti-inflammatory macrophages to degrade heme, and its expression is dependent on NRF2 translocation to the nucleus. In macrophages stimulated with conditioned media from pancreatic cancer cells, HO-1 protein levels increased, which correlated with higher NRF2 expression in the nuclear fraction. Significant differences in macrophage infiltration and HO-1 expression were detected in LSL-KrasG12D/+; Pdx-1-Cre (KC) mice, Nrf2 whole-body knockout (KO) mice and wildtype mice with pancreatitis. Since epigenetic modulation is a mechanism used by tumors to regulate the TME, using small molecules as epigenetic modulators to activate immune recognition is therapeutically desirable. When the bromodomain inhibitor I-BET-762 was used to treat macrophages or mice with pancreatitis, high levels of HO-1 were reduced. This study shows that bromodomain inhibitors can be used to prevent physiological responses to inflammation that promote tumorigenesis.

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Breaking the stromal barrier in pancreatic cancer: Advances and challenges

Cited by 3 publications

References 173 publications

Breaking Down Barriers in Drug Delivery by Stromal Remodeling Approaches in Pancreatic Cancer

Breaking Down Barriers in Drug Delivery by Stromal Remodeling Approaches in Pancreatic Cancer

Architectural organization and molecular profiling of 3D cancer heterospheroids and their application in drug testing

The BRD4 Inhibitor I-BET-762 Reduces HO-1 Expression in Macrophages and the Pancreas of Mice

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