RESUMEN

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.

Asunto(s)

Carcinoma Ductal Pancreático/tratamiento farmacológico , Integrinas/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias Pancreáticas/tratamiento farmacológico , Células Estrelladas Pancreáticas/metabolismo , Peptidomiméticos/farmacología , Animales , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Humanos , Integrinas/metabolismo , Masculino , Ratones , Ratones SCID , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Células Estrelladas Pancreáticas/patología , Peptidomiméticos/química , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina

RESUMEN

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-ß 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-ß- 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-ß 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.

Asunto(s)

Carcinoma Ductal Pancreático/metabolismo , Matriz Extracelular/metabolismo , Cadenas alfa de Integrinas/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Células Estrelladas Pancreáticas/metabolismo , Microambiente Tumoral , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Matriz Extracelular/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Neoplasias Pancreáticas/patología , Células Estrelladas Pancreáticas/patología

RESUMEN

Pancreatic stellate cells (PSCs) are the major contributor to the aggressive, metastatic, and resilient nature of pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis with a 5-year survival rate of 8%. PSCs constitute more than 50% of the tumor stroma in PDAC, where they induce extensive desmoplasia by secreting abundant extracellular matrix (ECM) proteins. In addition, they establish dynamic crosstalk with cancer cells and other stromal cells, which collectively supports tumor progression via various inter- and intracellular pathways. These cellular interactions and associated pathways may reveal novel therapeutic opportunities against this unmet clinical problem. In this review article, we discuss the role of PSCs in inducing tumor progression, their crosstalk with other cells, and therapeutic strategies to target PSCs.

Asunto(s)

Carcinoma Ductal Pancreático/metabolismo , Células Estrelladas Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/patología , Humanos

RESUMEN

Pancreatic stellate cells (PSCs) are the precursors of cancer-associated fibroblasts (CAFs), which potentiate pancreatic tumor growth and progression. In this study, we investigated whether Lipoxin A4 (LXA4), an endogenous bioactive lipid, can inhibit the differentiation of human PSCs (hPSCs) into CAF-like myofibroblasts and thereby hPSC-induced pro-tumorigenic effects. LXA4 significantly inhibited TGF-ß-mediated differentiation of hPSCs by inhibiting pSmad2/3 signalling. Furthermore, treatment with LXA4 abolished the paracrine effects (proliferation and migration of Panc-1 tumor cells) of hPSCs in vitro. These data demonstrated that LXA4 can interrupt pro-tumoral paracrine signalling of hPSCs. Furthermore, LXA4 treatment significant decreased the size and growth rate of 3D-heterospheroids comprised of hPSC and Panc-1 and these effects were exhibited due to inhibition of hPSC-induced collagen1 expression. In vivo, we examined the therapeutic efficacy of LXA4 in a co-injection (Panc-1 and hPSCs) subcutaneous tumor model. Intriguingly, LXA4 significantly abolished the tumor growth (either injected intratumor or intraperitoneally), attributed to a significant reduction in fibrosis, shown with collagen1 expression. Altogether, this study proposes LXA4 as a potent inhibitor for hPSCs which can be applied to reprogram tumor stroma in order to treat pancreatic cancer.

Asunto(s)

Reprogramación Celular/efectos de los fármacos , Lipoxinas/administración & dosificación , Neoplasias Pancreáticas/terapia , Células Estrelladas Pancreáticas/citología , Células Estrelladas Pancreáticas/trasplante , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Colágeno Tipo I/metabolismo , Terapia Combinada , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lipoxinas/farmacología , Ratones , Neoplasias Pancreáticas/metabolismo , Células Estrelladas Pancreáticas/efectos de los fármacos , Comunicación Paracrina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/farmacología

RESUMEN

Wound healing is a complex process, which ultimately leads to fibrosis if not repaired well. Pathologically very similar to fibrosis is the tumor stroma, found in several solid tumors which are regarded as wounds that do not heal. Integrins are heterodimeric surface receptors which control various physiological cellular functions. Additionally, integrins also sense ECM-induced extracellular changes during pathological events, leading to cellular responses, which influence ECM remodeling. The purpose and scope of this review is to introduce integrins as key targets for therapeutics and drug delivery within the scope of wound healing, fibrosis and the tumor stroma. This review provides a general introduction to the biology of integrins including their types, ligands, means of signaling and interaction with growth factor receptors. Furthermore, we highlight integrins as key targets for therapeutics and drug delivery, based on their biological role, expression pattern within human tissues and at cellular level. Next, therapeutic approaches targeting integrins, with a focus on clinical studies, and targeted drug delivery strategies based on ligands are described.

Asunto(s)

Antineoplásicos/farmacología , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Células del Estroma/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Animales , Antineoplásicos/química , Fibrosis/tratamiento farmacológico , Fibrosis/patología , Humanos , Neoplasias/patología , Células del Estroma/patología

RESUMEN

AIM: To develop novel peptide-based nanocomplexes (NCs) for delivery of anti-miRNA oligonucleotides to human-derived pancreatic stellate cells (hPSCs), precursors of cancer-associated fibroblasts. MATERIALS & METHODS: NCs of anti-miRNA oligonucleotides and cell-penetrating peptides (different variants) were formed and characterized. The effects of anti-miR-199a delivery on hPSC differentiation and 3D heterospheroid formation were investigated. RESULTS: Dimeric cell-penetrating peptide based NCs (NC-2) showed 130-fold higher uptake by hPSCs compared with monomer-based NCs (NC-1) and tenfold higher uptake compared with general fibroblasts and different pancreatic tumor cells. Interestingly, delivery of anti-miR-199a inhibited hPSC differentiation into cancer-associated fibroblasts and inhibited the size of 3D heterospheroids comprised of hPSCs and tumor cells. CONCLUSION: Our NCs present a highly efficient anti-miRNA delivery system to hPSCs to inhibit their protumorigenic activity.

RESUMEN

BACKGROUND: The HMGA2 protein has experimentally been linked to EMT and cancer stemness. Recent studies imply that tumour-stroma interactions regulate these features and thereby contribute to tumour aggressiveness. METHODS: We analysed 253 cases of pancreatic ductal adenocarcinoma (PDAC) and 155 cases of ampullary adenocarcinoma (AAC) for HMGA2 expression by IHC. The data were correlated with stroma abundance and supplemented by experimental studies. RESULTS: HMGA2 acts as an independent prognostic marker associated with a significantly shorter overall survival in both tumour types. Overall, HMGA2-positivity was more frequent in patients with PDAC than with AAC. The HMGA2 status in tumour cells significantly correlated with the abundance of PDGFRß-defined stroma cells. In vivo co-injection of Panc-1 cancer cells with pancreatic stellate cells increased tumour growth in a manner associated with increased HMGA2 expression. Furthermore, in vitro treatment of Panc-1 with conditioned media from PDGF-BB-activated stellate cells increased their ability to form tumour spheroids. CONCLUSIONS: This study identifies HMGA2 expression in tumour cells as an independent prognostic marker in PDAC and AAC. Correlative data analysis gives novel tissue-based evidence for a heterotypic cross-talk with stroma cells as a possible mechanism for HMGA2 induction, which is further supported by experimental models.

Asunto(s)

Adenocarcinoma/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Neoplasias del Conducto Colédoco/metabolismo , Proteína HMGA2/metabolismo , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/patología , Anciano , Ampolla Hepatopancreática , Animales , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Neoplasias del Conducto Colédoco/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Trasplante de Neoplasias , Neoplasias Pancreáticas/patología , Células Estrelladas Pancreáticas/metabolismo , Pronóstico , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células del Estroma/metabolismo , Tasa de Supervivencia

RESUMEN

Communication between stromal cells and tumor cells initiates tumor growth, angiogenesis, invasion, and metastasis. Stromal cells include cancer-associated fibroblasts, tumor-associated macrophages, pericytes, endothelial cells, and infiltrating immune cells. MicroRNAs (miRNAs) in the tumor microenvironment have emerged as key players involved in the development of cancer and its progression. miRNAs are small endogenous non-protein-coding RNAs that negatively regulate the expression of multiple target genes at post-transcriptional level and thereby control many cellular processes. In this review, we provide a comprehensive overview of miRNAs dysregulated in different stromal cells and their impact on the regulation of intercellular crosstalk in the tumor microenvironment. We also discuss the therapeutic significance potential of miRNAs to modulate the tumor microenvironment. Since miRNA delivery is quite challenging and the biggest hurdle for clinical translation of miRNA therapeutics, we review various non-viral miRNA delivery systems that can potentially be used for targeting miRNA to stromal cells within the tumor microenvironment.