Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma

Koikawa, Kazuhiro; Ohuchida, Kenoki; Ando, Yumiko; Kibe, Shin; Nakayama, Hiromichi; Takesue, Shin; Endo, Shunsuke; Abe, Toshiya; Okumura, Takashi; Iwamoto, Chika; Moriyama, Taiki; Nakata, Kohei; Miyasaka, Yoshihiro; Ohtsuka, Takao; Nagai, Eishi; Mizumoto, Kazuhiro; Hashizume, Makoto; Nakamura, Masafumi

doi:10.1016/j.canlet.2018.03.031

Cited by 57 publications

(62 citation statements)

References 45 publications

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“…21,27,28 Moreover, the decomposition of ECM leads to the release of ECM-bound factors, which, in turn, are involved in the regulation of pathological parameters, 29 angiogenesis or lymphangiogenesis, 30,31 chronic inflammation, 32 metastasis and tumour growth. There is considerable evidence that MMPs, particularly MMP-2, play a vital role in promoting tumour invasion, enabling the disintegration of epithelial tissue and cell migration or invasion.…”

Section: Discussionmentioning

confidence: 99%

“…As shown in Figure 2A Figure 2E). 20,21 To further investigate the role of MMP-2 in the stimulatory effects of insulin on cellular migration and invasion, a blockade study using MMP-2 siRNA was carried out with insulin treatment. As shown in Figure 2E, KRAS mutation induced the increased expression, but insulin stimulation had no effect.…”

Section: Involvement Of Mmp-2 In Insulin-induced Migration and Invamentioning

confidence: 99%

“…Further analysis demonstrated that the insulin-induced MMP-2 gelatinolytic activity is concentration-dependent in both HPNE and HPNE-mut-KRAS ( Figure 3A It has been suggested that MMP-2 is involved in the regulation of cell migration and invasion. 20,21 To further investigate the role of MMP-2 in the stimulatory effects of insulin on cellular migration and invasion, a blockade study using MMP-2 siRNA was carried out with insulin treatment. The interference efficiency of three siRNAs was evaluated via qRT-PCR and gelatin zymography, and siRNA#2 was selected for the following studies ( Figure 4A,B).…”

Section: Involvement Of Mmp-2 In Insulin-induced Migration and Invamentioning

confidence: 99%

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Insulin promotes invasion and migration of KRAS^G12D mutant HPNE cells by upregulating MMP‐2 gelatinolytic activity via ERK‐ and PI3K‐dependent signalling

et al. 2019

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Objectives: Hyperinsulinemia is a risk factor for pancreatic cancer, but the function of insulin in carcinogenesis is unclear, so this study aimed to elucidate the carcinogenic effects of insulin and the synergistic effect with the KRAS mutation in the early stage of pancreatic cancer. Materials and methods:A pair of immortalized human pancreatic duct-derived cells, hTERT-HPNE E6/E7/st (HPNE) and its oncogenic KRAS G12D variant, hTERT-HPNE E6/ E7/KRAS G12D /st (HPNE-mut-KRAS), were used to investigate the effect of insulin. Cell proliferation, migration and invasion were assessed using Cell Counting Kit-8 and transwell assays, respectively. The expression of E-cadherin, N-cadherin, vimentin and matrix metalloproteinases (MMP-2, MMP-7 and MMP-9) was evaluated by Western blotting and/or qRT-PCR. The gelatinase activity of MMP-2 and MMP-9 in conditioned media was detected using gelatin zymography. The phosphorylation status of AKT, GSK3β, p38, JNK and ERK1/2 MAPK was determined by Western blotting. Results: The migration and invasion ability of HPNE cells was increased after the intro-duction of the mutated KRAS gene, together with an increased expression of MMP-2.These effects were further enhanced by the simultaneous administration of insulin.The use of MMP-2 siRNA confirmed that MMP-2 was involved in the regulation of cell invasion. Furthermore, there was a concentration-and time-dependent increase in gelatinase activity after insulin treatment, which could be reversed by an insulin receptor tyrosine kinase inhibitor (HNMPA-(AM) 3 ). In addition, insulin markedly enhanced the phosphorylation of PI3K/AKT, p38, JNK and ERK1/2 MAPK pathways, with wortmannin or LY294002 (a PI3K-specific inhibitor) and PD98059 (a MEK1-specific inhibitor) significantly inhibiting the insulin-induced increase in MMP-2 gelatinolytic activity.

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Section: Discussionmentioning

confidence: 99%

Section: Involvement Of Mmp-2 In Insulin-induced Migration and Invamentioning

confidence: 99%

Section: Involvement Of Mmp-2 In Insulin-induced Migration and Invamentioning

confidence: 99%

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Insulin promotes invasion and migration of KRAS^G12D mutant HPNE cells by upregulating MMP‐2 gelatinolytic activity via ERK‐ and PI3K‐dependent signalling

et al. 2019

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“…The most conclusive evidence of the role of MMP2 in PDAC progression comes from subcutaneous models, in which the injection of shMMP2-silenced PANC1 cells resulted in smaller tumors compared to the injection of control shRNA transduced cells [84], whereas treatment with MMP2-blocking peptides limited tumor growth and angiogenesis [85].…”

Section: Gelatinases In Pdacmentioning

confidence: 99%

“…Indeed, the overexpression of MMP14 in mice expressing an activating Kras(G12D) mutation led to more large, dysplastic mucin-containing papillary lesions compared to the control Kras(G12D) mice (Table 3) [107]. Using subcutaneous models, MMP14 overexpression in cancer cells seems to reduce the cytotoxic effect of gemcitabine [108], whereas MMP14 inhibition in pancreatic stellate cells limits tumor growth [84]. Moreover, the cancer cell-specific overexpression of membrane-type 1 matrix metalloproteinase cytoplasmic tail binding protein-1 (MTCBP-1; MMP14 binding protein inhibiting its activity) restricts metastasis in orthotopic PDAC models, further suggesting that MMP14 may enhance tumor progression [109].…”

Section: Membrane-type Mmps In Pdacmentioning

confidence: 99%

Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?

Slapak

Duitman

Tekin

et al. 2020

Biology

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Pancreatic cancer is a dismal disorder that is histologically characterized by a dense fibrotic stroma around the tumor cells. As the extracellular matrix comprises the bulk of the stroma, matrix degrading proteases may play an important role in pancreatic cancer. It has been suggested that matrix metalloproteases are key drivers of both tumor growth and metastasis during pancreatic cancer progression. Based upon this notion, changes in matrix metalloprotease expression levels are often considered surrogate markers for pancreatic cancer progression and/or treatment response. Indeed, reduced matrix metalloprotease levels upon treatment (either pharmacological or due to genetic ablation) are considered as proof of the anti-tumorigenic potential of the mediator under study. In the current review, we aim to establish whether matrix metalloproteases indeed drive pancreatic cancer progression and whether decreased matrix metalloprotease levels in experimental settings are therefore indicative of treatment response. After a systematic review of the studies focusing on matrix metalloproteases in pancreatic cancer, we conclude that the available literature is not as convincing as expected and that, although individual matrix metalloproteases may contribute to pancreatic cancer growth and metastasis, this does not support the generalized notion that matrix metalloproteases drive pancreatic ductal adenocarcinoma progression.

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Adipose‐derived mesenchymal stem cells differentiate into pancreatic cancer‐associated fibroblasts in vitro

et al. 2020

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Cancer-associated fibroblasts (CAFs) are key components of the dense, proliferating stroma observed in pancreatic ductal adenocarcinoma (PDAC), and CAF subpopulations drive tumor heterogeneity and play a major role in PDAC progression and drug resistance. CAFs consist of heterogenous subpopulations such as myoblastic CAF (myCAF) and inflammatory CAF (iCAF), and each has distinct essential roles. However, it is not clear how CAF subpopulations are formed in PDAC. Adiposederived MSCs (AD-MSCs), which possess a high multilineage potential and self-renewal capacity, are reported to be one of the in vivo CAF sources. Here, we aimed to investigate whether AD-MSCs can act as precursors for CAFs in vitro. We recorded morphological features and collected omics data from two in vitro co-culture models for recapitulating clinical PDAC. Additionally, we tested the advantages of the co-culture model in terms of accurately modeling morphology and CAF heterogeneity. We showed that AD-MSCs differentiate into two distinct CAF subpopulations: Direct contact co-culture with PDAC cell line Capan-1 induced differentiation into myCAFs and iCAFs, while indirect co-culture induced differentiation into only iCAFs. Using these co-culture systems, we also identified novel CAF markers that may be helpful for elucidating the mechanisms of CAFs in the tumor microenvironment (TME). In conclusion, AD-MSCs can differentiate into distinct CAF subtypes depending on the different co-culture conditions in vitro, and the identification of potential CAF markers may aid in future investigations of the mechanisms underlying the role of CAFs in the TME.

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Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma

Cited by 57 publications

References 45 publications

Insulin promotes invasion and migration of KRAS^G12D mutant HPNE cells by upregulating MMP‐2 gelatinolytic activity via ERK‐ and PI3K‐dependent signalling

Insulin promotes invasion and migration of KRAS^G12D mutant HPNE cells by upregulating MMP‐2 gelatinolytic activity via ERK‐ and PI3K‐dependent signalling

Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?

Adipose‐derived mesenchymal stem cells differentiate into pancreatic cancer‐associated fibroblasts in vitro

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Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma

Cited by 57 publications

References 45 publications

Insulin promotes invasion and migration of KRASG12D mutant HPNE cells by upregulating MMP‐2 gelatinolytic activity via ERK‐ and PI3K‐dependent signalling

Insulin promotes invasion and migration of KRASG12D mutant HPNE cells by upregulating MMP‐2 gelatinolytic activity via ERK‐ and PI3K‐dependent signalling

Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?

Adipose‐derived mesenchymal stem cells differentiate into pancreatic cancer‐associated fibroblasts in vitro

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Product

Resources

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Insulin promotes invasion and migration of KRAS^G12D mutant HPNE cells by upregulating MMP‐2 gelatinolytic activity via ERK‐ and PI3K‐dependent signalling

Insulin promotes invasion and migration of KRAS^G12D mutant HPNE cells by upregulating MMP‐2 gelatinolytic activity via ERK‐ and PI3K‐dependent signalling