Desmoplasia in Pancreatic Cancer. Can We Fight It?

Merika, Eirini; Syrigos, Kostas; Saif, Muhammad Wasif

doi:10.1155/2012/781765

Cited by 54 publications

(53 citation statements)

References 79 publications

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“…The function of desmoplastic stroma is likely dynamic during cancer progression and its heterogeneous cellular and non-cellular constituents change in relation to the evolving genetic landscape of cancer cells. In this regard, several studies have suggested that αSMA + myofibroblasts and type I collagen associated with tumor fibrosis are tumor promoting in solid tumors including PDAC (Angeli et al, 2009; Karnoub et al, 2007; Merika et al, 2012; Vong and Kalluri, 2011). We demonstrate that depletion of αSMA + myofibroblasts resulted in multiple adverse outcomes leading to poor survival.…”

Section: Resultsmentioning

confidence: 99%

Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival

et al. 2014

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Summary Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts but their functional contribution remains unknown. Transgenic mice with ability to delete αSMA+ myofibroblasts in pancreatic cancer were generated. Depletion starting at either non-invasive precursor (PanIN) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition and cancer stem cells, with diminished animal survival. In PDAC patients, lower myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4+Foxp3+ Tregs was observed in myofibroblasts depleted mouse tumors. While myofibroblasts depleted tumors did not respond to Gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.

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Section: Resultsmentioning

confidence: 99%

Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival

et al. 2014

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“…Pancreatic tumors are typically characterized by a high desmoplastic reaction (42). Desmoplasia plays an important role to initiate cross-talk between stromal-cancer cells, limit the delivery and effectiveness of chemotherapy, and induce chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer

et al. 2015

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The management of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to lack of an efficient therapy and development of chemoresistance to the current standard therapy, gemcitabine (GEM). Recent studies implicate the intimate reciprocal interactions between epithelia and underlying stroma due to paracrine Sonic hedgehog (SHH) signaling in producing desmoplasia and chemoresistance in PDAC. Herein, we report for the first time that a nonsteroidal drug, ormeloxifene (ORM), has potent anti-cancer properties and depletes tumor-associated stromal tissue by inhibiting the SHH signaling pathway in PDAC. We found that ORM inhibited cell proliferation and induced death in PDAC cells, which provoked us to investigate the combinatorial effects of ORM with GEM at the molecular level. ORM caused potent inhibition of the SHH signaling pathway via downregulation of SHH and its related important downstream targets such as Gli-1, SMO, PTCH1/2, NFκB, p-AKT and Cyclin D1. ORM potentiated the anti-tumorigenic effect of GEM by 75% in PDAC xenograft mice. Further, ORM depleted tumor-associated stroma in xenograft tumor tissues by inhibiting the SHH cellular signaling pathway and mouse/human collagen I expression. Xenograft tumors treated with ORM in combination with GEM restored the tumor suppressor miR-132, and inhibited stromal cell infiltration into the tumor tissues. Additionally, invasiveness of tumor cells co-cultivated with TGFβ-stimulated human pancreatic stromal cells was effectively inhibited by ORM treatment alone or in combination with GEM. We propose that ORM has high therapeutic index and in a combination therapy with GEM it possesses great promise as a treatment of choice for PDAC/pancreatic cancer.

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“…Additionally, our study shows that a PLGA-CUR formulation was also highly effective in suppressing angiogenesis as indicated by a decrease in CD31(+) microvessel density (Figure 7). The PLGA-CUR induced effects were accompanied by enhanced recruitment of macrophages (Figure 7) that infiltrate the tumor, induce T cell anti-tumor immunity [43] and facilitate the depletion of the tumor stroma [54]. All together, our in vitro results demonstrate that PLGA-CUR NPs exhibit greater anti-cancer potential over free CUR by inhibiting AKT and STAT3, and inducing apoptosis, which enhance its translational value as therapeutic agents.…”

Section: Discussionmentioning

confidence: 88%

Anti-cancer activity of curcumin loaded nanoparticles in prostate cancer

Yallapu¹,

Khan²,

Maher³

et al. 2014

Biomaterials

235

153

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Prostate cancer is the most commonly diagnosed cancer disease in men in the Unites States and its management remains challenge in everyday oncology practice. Thus, advanced therapeutic strategies are required to treat prostate cancer patients. Curcumin (CUR) is a promising anticancer agent for various cancer types. The objective of this study was to evaluate therapeutic potential of novel poly(lactic-co-glycolic acid)- CUR nanoparticles (PLGA-CUR NPs) for prostate cancer treatment. Our results indicate that PLGA-CUR NPs efficiently internalize in prostate cancer cells and release biologically active CUR in cytosolic compartment of cells for effective therapeutic activity. Cell proliferation (MTS), clonogenic, and Western blot analyses reveal that PLGA-CUR NPs can effectively inhibit proliferation and colony formation ability of prostate cancer cells than free CUR. PLGA-CUR NPs showed superior tumor regression compared to CUR in xenograft mice. Further investigations reveal that PLGA-CUR NPs inhibit nuclear β-catenin and AR expression in cells and in tumor xenograft tissues. It also suppresses STAT3 and AKT phosphorylation and leads to apoptosis via inhibition of key anti-apoptotic proteins, MCL-1, Bcl-xL and caused induction of PARP cleavage. Additionally, PLGA-CUR NPs significant downregulation of oncogenic miR21 and up-regulation of miR-205 was observed with PLGA-CUR NPs treatment as determined by RT-PCR and in situ hybridization analyses. A superior anti-cancer potential was attained with PSMA antibody conjugated PLGA-CUR NPs in prostate cancer cells and a significant tumor targeting of 131I labelled PSMA antibody was achieved with PLGA-CUR NPs in prostate cancer xenograft mice model. In conclusion, PLGA-CUR NPs can significantly accumulate and exhibit superior anticancer activity in prostate cancer.

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Desmoplasia in Pancreatic Cancer. Can We Fight It?

Cited by 54 publications

References 79 publications

Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival

Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival

Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer

Anti-cancer activity of curcumin loaded nanoparticles in prostate cancer

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