The impact of hypoxia in pancreatic cancer invasion and metastasis

Yuen, Angela; Díaz, Begoña

doi:10.2147/hp.s52636

Cited by 58 publications

(40 citation statements)

References 144 publications

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“…In this work we identified STK33 as an essential HSP90 client that participates in a complex tumor angiogenic program coordinated by the chaperone. Our study has revealed STK33 as an essential molecule for progression of pancreatic and colorectal cancers in which the tumor environment was reported to be highly hypoxic [ 33 , 34 ]. Accordingly, we found a predominantly strong STK33 expression in all investigated human CRCs and PDACs.…”

Section: Discussionmentioning

confidence: 99%

STK33 participates to HSP90-supported angiogenic program in hypoxic tumors by regulating HIF-1α/VEGF signaling pathway

Liu

Steinestel

Rouhi³

et al. 2017

Oncotarget

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Lately, the HSP90 client serine/threonine kinase STK33 emerged to be required by cancer cells for their viability and proliferation. However, its mechanistic contribution to carcinogenesis is not clearly understood. Here we report that elevated STK33 expression correlates with advanced stages of human pancreatic and colorectal carcinomas. Impaired proliferation and augmented apoptosis associated with genetic abrogation of STK33 were paralleled by decreased vascularization in tumor xenografts. In line with this, ectopic STK33 not only promoted tumor growth after pharmacologic inhibition of HSP90 using structurally divergent small molecules currently in clinical development, but also restored blood vessel formation in vivo. Mechanistic studies demonstrated that HSP90-stabilized STK33 interacts with and regulates hypoxia-driven accumulation and activation of HIF-1α as well as secretion of VEGF-A in hypoxic cancer cells. In addition, our study reveals a putative cooperation between STK33 and other HSP90 client protein kinases involved in molecular and cellular events through which cancer cells ensure their survival by securing the oxygen and nutrient supply. Altogether, our findings indicate that STK33 interferes with signals from hypoxia and HSP90 to promote tumor angiogenesis and tumor growth.

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Section: Discussionmentioning

confidence: 99%

STK33 participates to HSP90-supported angiogenic program in hypoxic tumors by regulating HIF-1α/VEGF signaling pathway

Liu

Steinestel

Rouhi³

et al. 2017

Oncotarget

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“…It has been shown clinically with hypoxia radiotracers and hypoxic probes that most pancreatic tumors are hypoxic [22,23]. Hypoxia is one of the factors that has been proposed as an indicator for pancreatic tumor metastasis and is associated with poor prognosis and the epithelial to mesenchymal transition [24]. The mouse model used in this study generated tumors with large hypoxic regions, from which gemcitabine and 5-FU were largely excluded, highlighting the need for effective options for this refractory population.…”

Section: Plos Onementioning

confidence: 99%

Comparing the intra-tumoral distribution of Gemcitabine, 5-Fluorouracil, and Capecitabine in a murine model of pancreatic ductal adenocarcinoma

et al. 2020

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To develop a technique to compare the intra-tumoral distribution of the drug gemcitabine, its surrogate [ 18 F]-fluoroarabinocytosine ([ 18 F]-FAC) and related chemotherapeutics 5-FU and capecitabine in a pre-clinical model of pancreatic ductal adenocarcinoma (PDAC). Experimental design Using a KPC-organoid derived model of PDAC, we obtained autoradiographic images of the tumor distribution of, [ 14 C]-gemcitabine, [ 14 C]-5-FU, [ 3 H]-capecitabine. These were compared indirectly by co-administering [ 18 F]-FAC, a close analog of gemcitabine with a proven equivalent intra-tumor distribution. The short half-life of 18 F allows for clean separation of 3 H/ 14 C labeled drugs in specimens by dual isotope digital autoradiography. Autoradiographic images of [ 14 C]-gemcitabine, [ 3 H]-capecitabine and [ 14 C]-5-FU were each correlated to [ 18 F]-FAC on a pixel-by-pixel basis. The tumor drug penetration was compared using cumulative histograms. Results Gemcitabine distribution correlated strongly with FAC as expected. 5-FU also gave a similar microdistribution to that of FAC, whereas no correlation was found between capecitabine or its metabolic products and FAC distribution. Accumulation of Gemcitabine and 5-FU was lower in hypoxic regions of the tumor, whereas no such correlation was observed for capecitabine and its metabolites.

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“…Indeed, accumulation of intracellular hypoxia-inducible factors ( e.g. HIF-1α) are correlated with poor tumor differentiation and fibrotic foci in PDA [47, 48] and have been shown to promote pancreatic cancer stem cell (CSC) expansion, including CD133 + CSCs that are known to determine the metastatic phenotype of individual tumors through HIF-1α-dependent activation of the Notch signaling pathway [34, 49–53]. Treatments that decrease the hypoxic stress of the PDA microenvironment could significantly improve endogenous immune responses and immunotherapy efficacy, and have also been shown to improve response to radiotherapy and chemotherapy [53–55].…”

Section: Introductionmentioning

confidence: 99%

Focused ultrasound for immuno-adjuvant treatment of pancreatic cancer: An emerging clinical paradigm in the era of personalized oncotherapy

Maloney

Khokhlova

Pillarisetty

et al. 2017

International Reviews of Immunology

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Current clinical treatment regimens, including many emergent immune strategies (e.g. checkpoint inhibitors) have done little to affect the devastating course of pancreatic ductal adenocarcinoma (PDA). Clinical trials for PDA often employ multi-modal treatment, and have started to incorporate stromal-targeted therapies, which have shown promising results in early reports. Focused ultrasound (FUS) is one such therapy that is uniquely equipped to address local and systemic limitations of conventional cancer therapies as well as emergent immune therapies for PDA. FUS methods can non-invasively generate mechanical and/or thermal effects that capitalize on the unique oncogenomic/proteomic signature of a tumor. Potential benefits of FUS therapy for PDA include: 1) emulsification of targeted tumor into undenatured antigens in situ, increasing dendritic cell maturation, and increasing intra-tumoral CD8+/ T regulatory cell ratio and CD8+ T cell activity; 2) reduction in intra-tumoral hypoxic stress; 3) modulation of tumor cell membrane protein localization to enhance immunogenicity; 4) modulation of the local cytokine milieu toward a Th1-type inflammatory profile; 5) up-regulation of local chemoattractants; 6) remodeling the tumor stroma; 7) localized delivery of exogenously packaged immune-stimulating antigens, genes and therapeutic drugs. While not all of these results have been studied in experimental PDA models to date, the principles garnered from other solid tumor and disease models have direct relevance to the design of optimal FUS protocols for PDA. In this review, we address the pertinent limitations in current and emergent immune therapies that can be improved with FUS therapy for PDA.

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The impact of hypoxia in pancreatic cancer invasion and metastasis

Cited by 58 publications

References 144 publications

STK33 participates to HSP90-supported angiogenic program in hypoxic tumors by regulating HIF-1α/VEGF signaling pathway

STK33 participates to HSP90-supported angiogenic program in hypoxic tumors by regulating HIF-1α/VEGF signaling pathway

Comparing the intra-tumoral distribution of Gemcitabine, 5-Fluorouracil, and Capecitabine in a murine model of pancreatic ductal adenocarcinoma

Focused ultrasound for immuno-adjuvant treatment of pancreatic cancer: An emerging clinical paradigm in the era of personalized oncotherapy

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