Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin α5 (ITGA5) receptor in the PDAC stroma. ITGA5 was overexpressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models.

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Pancreatic ductal adenocarcinoma (PDAC) is the deadliest tumor due to its highly abundant tumor stroma. Pancreatic stellate cells (PSCs) are considered precursor cells of cancer‐associated fibroblasts (CAFs), which induce tumor progression, invasion, and metastasis. In this study, we investigated the role of integrin subunit α (ITGA) 11, the receptor for collagen type I, in tumor stroma interaction. Clinical sample analysis showed that ITGA11 was overexpressed by CAFs in PDAC stroma, as shown with colocalization immunostaining with α—smooth muscle actin. In contrast, there was no expression in healthy pancreas. Public transcriptomic data confirmed a reduced expression of ITGA11 in healthy pancreas and adjacent nontumoral tissues compared with human tumor tissues. Primary human PSCs (hPSCs) activated with either TGF‐β or pancreatic cancer cell (PANC‐1)–conditioned medium (CM) resulted in the significant up‐regulation of ITGA11 and various CAF markers. Furthermore, short hairpin RNA (shRNA)‐mediated stable ITGA11 knockdown (shITGA11) in hPSCs significantly inhibited TGF‐β– and PANC‐1 CM–mediated activation at both gene and protein levels of extracellular matrix, cytokines, and adhesion molecules. Additionally, shITGA11 hPSCs had a reduced migration and contractility compared with shRNA control (shCTR) PSCs. Furthermore, we investigated the effect of ITGA11 on the paracrine effects of hPSCs. Interestingly, the CM from shITGA11 hPSCs, activated with either TGF‐β or PANC‐1 CM, caused tumor cells to migrate and invade lesser compared with their counterpart, activated shCTR PSCs. In summary, this study presents ITGA11 as an interesting stromal therapeutic target that plays a crucial role in the regulation of the differentiation of PSCs into CAFs and paracrine effects.—Schnittert, J., Bansal, R., Mardhian, D. F., van Baarlen, J., Östman, A., Prakash, J. Integrin α11 in pancreatic stellate cells regulates tumor stroma interaction in pancreatic cancer. FASEB J. 33, 6609–6621 (2019). http://www.fasebj.org

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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.

Hydrogel-based wound dressings are often chosen for healing diabetic foot ulcers (DFU) in combination with herbal extracts. Moringa oleifera leaf (MOL) extract is a potent herb containing antimicrobial and anti-inflammatory bioactive substances. In this work, wound dressings based on polyvinyl alcohol (PVA), MOL extract, and graphene oxide (GO) were developed for DFU wound dressing. The PVA/MOL/GO hydrogel was synthesized using four cycles of a freeze–thaw process with varying concentrations of MOL extract. All hydrogels showed a water content of 83–88% and an equilibrium swelling ratio between 155–171%. After degradation in phosphate-buffered saline, the hydrogels showed a more open porous structure. We observed a degradation rate of 26–28%. Although the increase in MOL extract reduced the tensile strength of the hydrogel, the addition of GO increased the tensile strength. The PVA/MOL/GO hydrogel showed the highest antibacterial activity, with a reduction of 94% Gram-positive S. aureus and 82% Gram-negative E. coli. Finally, all samples possessed appropriate cytocompatibility with cell viability reaching 83–135% in 3T3L1 mouse fibroblast cells. This result was verified by in vitro wound-healing analysis performed by scratch assay. This study presents the potency of combined PVA, MOL, and GO as a biocompatible DFU wound dressing.

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Nano Zirconia (ZrO2) has been used in dental implants due to having excellent mechanical properties and biocompatibility that match the requirements for the purpose. Zirconia undergoes phase transformation during heating: monoclinic (room temperature to 1170 °C), tetragonal (1170 °C to 2370 °C), and cubic (>2370 °C). Most useful mechanical properties can be obtained when zirconia is in a multiphase form or in partially stabilized zirconia (PSZ), which is achieved by adding small amounts of a metal oxide dopant, such as MgO (magnesia). This study aimed to synthesize nano Mg-PSZ from a local resource found in West Kalimantan, Indonesia, and examine its structural stability, biochemical stability, and mechanical properties. Nano Mg-PSZ was prepared from a zircon local to Indonesia, from West Kalimantan Province, MgSO4∙7H2O, and polyethylene glycol (PEG)-6000 was used as a template. The obtained t-ZrO2 after calcination at 800 °C was shown to be stable at room temperature. The highest percentage of the t-ZrO2 phase was obtained at Zr0.95Mg0.05O2 with a variation of 99.5%. The hardness of Mg-PSZ increased from 554 MPa for ZrO2 without MgO doping to 5266 MPa for ZrO2 with a doping of 10% MgO. An in vitro biodegradation test showed that the greater the concentration of MgO in doping the ZrO2, the greater the degradation resistance of Mg-PSZ in simulated body fluid (SBF) solution.