Targeting Pancreatic Stellate Cells in Cancer

Schnittert, Jonas; Bansal, Ruchi; Prakash, Jai

doi:10.1016/j.trecan.2019.01.001

Cited by 113 publications

(106 citation statements)

References 120 publications

(156 reference statements)

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“…Aligned extracellular fibers in these environments allow metastatic invasion and persistent cell migration. In contrast, the physiologically normal stroma is naturally randomly oriented and tumor suppressive [47][48][49] . Strategies to ablate the culprit cancer associated fibroblasts (CAF) have indeed reduced stroma but offered no benefit to pancreatic ductal adenocarcinoma (PDAC) patients 50 , or in some cases even dangerously promoted cancer progression 51,52 .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, there is growing appreciation for "stroma normalization," i.e. reinstitution of physiological ECM, and not its elimination that is expected to impart clinical benefit 48,[53][54][55][56][57] . A direct route to achieve stroma normalization is first understanding the biophysical links that perpetuate desmoplastic expansion, and second develop informed intervention strategies that dissuade this expansion.…”

Section: Discussionmentioning

confidence: 99%

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Force-exerting lateral protrusions in fibroblastic cell contraction

Padhi

Singh

Franco‐Barraza

et al. 2019

Preprint

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Aligned extracellular matrix fibers impart an elongated cell morphology and enable fibroblasts to undergo myofibroblastic activation. Yet the biomechanical intricacies that are associated with this microenvironmental phenomenon are unknown. Here, we identify a new role of lateral protrusions, originating anywhere along elongated fibroblastic cells, which apply fiber-deflecting contractile forces. Using aligned fiber networks that serve as force sensors, we quantitate the role of lateral nano-projections (twines) that mature into "perpendicular lateral protrusions" (PLPs) through the formation of twine-bridges, thus allowing elongated cells to spread laterally and effectively contract. Using quantitative microscopy at high spatiotemporal resolution, we show that twines of varying lengths can originate from stratification of cyclic actin waves traversing along the entire length of the cell. Primary twines swing freely in 3D and engage with neighboring extracellular fibers in interaction times of seconds. Once engaged, an actin lamellum grows along the length of primary twine and re-stratifies to form a secondary twine. Engagement of secondary twine with the neighboring fiber leads to the formation of twine-bridge, a critical step in providing a conduit for actin to advance along and populate the twine-bridge. Through arrangement of fiber networks in varying configurations, we confirm that anisotropic fibrous environments are fertile for PLP dynamics, and importantly force-generating PLPs are oriented perpendicular to the parent cell body. Furthermore, cell spreading onto multiple fibers and myofibroblastic-like contraction occur through PLPs. Our identification of force exertion by PLPs identifies a possible explanation for cancer-associated desmoplastic expansion, at single-cell resolution, thus providing new clinical intervention opportunities.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Force-exerting lateral protrusions in fibroblastic cell contraction

Padhi

Singh

Franco‐Barraza

et al. 2019

Preprint

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“…PSCs are known to migrate to the invasive site as well as contract ECM in the tumor microenvironment leading to high stiffness [11]. We therefore examined the effect of FGF2-SPIONs on the hPSCs migration using scratch assay and TGF-β-induced contraction of hPSCs in 3D collagen gel.…”

Section: Fgf2-spions Inhibited the Migration And Contraction Of Hpscsmentioning

confidence: 99%

“…In addition, CAFs produce and remodel extracellular matrix (ECM), creating an impenetrable environment for chemotherapy and facilitating the formation of hypoxic and hypovascular network [9]. The main precursor cells of CAFs in PDAC are pancreatic stellate cells (PSCs) [11]. They are one of resident cells in the exocrine pancreas participating in the pathogenesis in major disorders, after transforming from quiescent state to activated state [12].…”

Section: Introductionmentioning

confidence: 99%

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FGF2 engineered SPIONs attenuate tumor stroma and potentiate the effect of chemotherapy in 3D heterospheroidal model of pancreatic tumor

Mardhian¹,

Vrynas²,

Storm³

et al. 2020

Nanotheranostics

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Pancreatic ductal adenocarcinoma (PDAC), characterized with abundant tumor stroma, is a highly malignant tumor with poor prognosis. The tumor stroma largely consists of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), and is known to promote tumor growth and progression as well as acts as a barrier to chemotherapy. Inhibition of tumor stroma is highly crucial to induce the effect of chemotherapy. In this study, we delivered fibroblast growth factor 2 (FGF2) to human pancreatic stellate cells (hPSCs), the precursors of CAFs, using superparamagnetic iron oxide nanoparticles (SPIONs). FGF2 was covalently conjugated to functionalized PEGylated dextran-coated SPIONs. FGF2-SPIONs significantly reduced TGF-β induced hPSCs differentiation (α-SMA and collagen-1 expression) by inhibiting pSmad2/3 signaling and inducing ERK1/2 activity, as shown with western blot analysis. Then, we established a stroma-rich self-assembling 3D heterospheroid model by co-culturing PANC-1 and hPSCs in 3D environment. We found that FGF2-SPIONs treatment alone inhibited the tumor stroma-induced spheroid growth. In addition, they also potentiated the effect of gemcitabine, as shown by measuring the spheroid size and ATP content. These effects were attributed to the reduced expression of the hPSC activation and differentiation marker, α-SMA. Furthermore, to demonstrate an application of SPIONs, we applied an external magnetic field to spheroids while incubated with FGF2-SPIONs. This resulted in an enhanced effect of gemcitabine in our 3D model. In conclusion, this study presents a novel approach to target FGF2 to tumor stroma using SPIONs and thereby enhancing the effect of gemcitabine as demonstrated in the complex 3D tumor spheroid model.

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Enzyme‐Activated Prodrug‐Based Smart Liposomes Specifically Enhance Tumor Hemoperfusion with Efficient Drug Delivery to Pancreatic Cancer Cells and Stellate Cells

Duan

Song

et al. 2021

Adv Funct Materials

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Tumor‐specific enhanced delivery of chemotherapeutics and modulators to tumor cells and activated pancreatic stellate cells (aPSCs), respectively, represents safer and more effective therapy for pancreatic cancer. Herein, a membrane type 1‐matrix metalloproteinase (MT1‐MMP)‐cleavable spacer is used to assemble low‐density cRGDfK onto thermosensitive liposomes loaded with phosphorylated calcipotriol (PCAL) and doxorubicin (DOX), yielding MR‐T‐PD. The liposome‐linked cRGDfK prodrug on MR‐T‐PD surface is first activated by MT1‐MMP, which is selectively expressed on tumor endothelial cells, to release cRGDfK. The free cRGDfK specifically promotes tumor angiogenesis, leading to 3.4‐fold higher accumulation and a wider distribution of MR‐T‐PD in tumors. Furthermore, MR‐T‐PD rapidly releases PCAL and DOX into the interstitium under heat treatment. The released DOX enters tumor cells to induce apoptosis, whereas the PCAL prodrug is converted to CAL by alkaline phosphatase on the surface of aPSCs; CAL can then enter aPSCs to induce quiescence and promote the antitumor effect of DOX. Finally, by enhancing the exposure of DOX and CAL to tumor cells and aPSCs, respectively, in a tumor‐specific manner, MR‐T‐PD exerts superior efficacy (a 5.9‐fold decrease in tumor weight) without causing additional side effects. Overall, this prodrug‐based smart liposome system represents a promising paradigm for pancreatic cancer therapy.

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Targeting Pancreatic Stellate Cells in Cancer

Cited by 113 publications

References 120 publications

Force-exerting lateral protrusions in fibroblastic cell contraction

Force-exerting lateral protrusions in fibroblastic cell contraction

FGF2 engineered SPIONs attenuate tumor stroma and potentiate the effect of chemotherapy in 3D heterospheroidal model of pancreatic tumor

Enzyme‐Activated Prodrug‐Based Smart Liposomes Specifically Enhance Tumor Hemoperfusion with Efficient Drug Delivery to Pancreatic Cancer Cells and Stellate Cells

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