Enhanced CXCL12/CXCR4 signaling increases tumor progression in radiation‑resistant pancreatic cancer

Kato, Toyonori; Matsuo, Yoichi; Ueda, Gaiko; Murase, Hiromichi; Aoyama, Yuichi; Omi, Kan; Hayashi, Yuichi; Imafuji, Hiroyuki; Saito, Kenta; Morimoto, Mamoru; Ogawa, Ryo; Takahashi, Hiroki; Takiguchi, Shuji

doi:10.3892/or.2022.8279

Cited by 11 publications

(5 citation statements)

References 57 publications

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“…Inhibition of Akt activity in the Gem-R PaCa cells suppressed invasive potential. While several pathways, including CXCL12/CXCR4 signaling ( 30 ) and NF- κ B ( 31 ), as well as Akt, are reported to be involved in the invasive potential of cancer, the enhancement of the Akt pathway by upregulation of ILK may be involved in the enhancement of the invasive potential of Gem-R PaCa cells.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of integrin‑linked kinase enhances tumor progression in gemcitabine‑resistant pancreatic cancer

et al. 2023

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Pancreatic cancer (PaCa) tends to be resistant to chemotherapy and is associated with a very poor prognosis. It has been previously reported by the authors that integrin-linked kinase (ILK) is a prognostic factor in PaCa. ILK expression was examined in a newly established gemcitabine (Gem)-resistant (Gem-R) PaCa cell line and it was demonstrated that ILK expression was upregulated compared with that in Gem-sensitive (Gem-S) cells. In the present study, the effects of increased ILK expression in Gem-R PaCa cells were evaluated and it was examined whether compound 22 (Cpd22), an ILK inhibitor, exerted antitumor effects not only in Gem-S cells but also in Gem-R cells. Reverse transcription-quantitative polymerase chain reaction and western blotting revealed that ILK expression was higher in Gem-R PaCa cells than in Gem-S PaCa cells. Cpd22 inhibited the growth of PaCa cells in a concentration-dependent manner. Cpd22 also inhibited the growth of Gem-R PaCa cells. The invasive and angiogenic potential of Gem-R PaCa cells was enhanced compared with that in Gem-S cells; however, ILK small interfering RNA and Cpd22 treatment suppressed this enhancement of invasive potential compared with that in Gem-S cells. The addition of Cpd22 to Gem also improved the sensitivity of Gem-R cell lines to Gem. Furthermore, enhanced Akt signaling was associated with increased malignancy in Gem-R cell lines. In conclusion, ILK was upregulated with resistance and may be involved in tumor angiogenesis, invasive potential, and chemotherapy resistance, which were all suppressed by Cpd22 treatment. Thus, Cpd22 may be a novel therapeutic agent for the treatment of PaCa.

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Section: Discussionmentioning

confidence: 99%

Upregulation of integrin‑linked kinase enhances tumor progression in gemcitabine‑resistant pancreatic cancer

et al. 2023

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“…SDF-1 activates downstream signaling pathways, such as PAM and ERK1/2, and enhances cancer cell survival, proliferation, and chemotaxis by binding to its receptor CXCR4 ( 23 ). Previous studies have shown that high expression of SDF-1/CXCR4 is correlated with poor survival in various tumors, such as colorectal cancer ( 24 ), prostate cancer ( 25 ), pancreatic cancer ( 26 ), and breast cancer ( 27 ). However, limited data have reported the value of SDF-1/CXCR4 in predicting chemotherapy response.…”

Section: Discussionmentioning

confidence: 99%

SDF-1 expression and tumor-infiltrating lymphocytes identify clinical subtypes of triple-negative breast cancer with different responses to neoadjuvant chemotherapy and survival

Wang

Ji²,

Gong³

et al. 2022

Front. Immunol.

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BackgroundIn this study, we investigated the prediction and prognostic value of SDF-1 for triple-negative breast cancer (TNBC) patients who underwent neoadjuvant chemotherapy (NAC) following standard radical surgery.MethodsA total of 303 TNBC patients were included in this study. The NAC regimen was weekly paclitaxel plus carboplatin (PC) for all patients. SDF-1 and CXCR4 expression were measured at baseline and surgery via enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC), respectively. Correlations between variables and treatment response were studied, and Cox proportional hazards regression analysis was implemented for prognostic evaluation.ResultsOf the 303 patients, 103 (34.0%) experienced pathological complete response (pCR) after completion of NAC. Serum SDF-1 expression before NAC was significantly correlated with the abundance of TILs. A higher pCR rate was more likely to be observed in patients with lower serum SDF-1 levels before NAC (P=0.001, OR=0.997, 95% CI: 0.996-0.999) and higher levels of TILs (P=0.005). In the multivariate survival model for nonpCR patients, serum SDF-1 expression at surgery served as an independent prognostic value for survival (high level, HR=1.980, 95% CI: 1.170-3.350, low level was used as a reference; P=0.011). Additionally, the predictive and prognostic value of serum SDF-1 expression was significant in patients with high abundance of TILs but not in patients with low abundance of TILs.ConclusionsThis study contributes to the clarification of the value of serum SDF-1 to predict pCR and survival for TNBC patients who underwent NAC. This new serum marker, together with TILs, might help identify clinical subtypes of TNBC with different treatment responses and survival and play an important role in tailoring and modifying the NAC strategy for advanced TNBCs in the future.

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“…IHC staining using an anti-Girdin antibody was performed in PaCa tissues obtained from surgically resected specimens at Nagoya City University Graduate School of Medical Sciences. The IHC staining procedure was performed as previously described (20).…”

Section: Methodsmentioning

confidence: 99%

Girdin regulates both migration and angiogenesis in pancreatic cancer cell lines

et al. 2023

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Girdin, an actin-binding protein, is reportedly involved in the invasion and angiogenesis of various cancers. It has been suggested that the flavonoid Scutellarin (SCU) inhibits Girdin signaling. In the present study, the function and therapeutic applications of Girdin in pancreatic cancer (PaCa) were investigated. Immunohistochemical staining of Girdin in resected PaCa specimens from the Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science showed that high Girdin expression was associated with poor overall survival and relapse-free survival, as well as with T factor, indicating invasion into the surrounding tissues. On the other hand, Girdin was highly expressed in almost all PaCa cell lines, and the migration ability of Girdin-knockdown cell lines was decreased even under epidermal growth factor (EGF) stimulation. In addition, SCU suppressed PaCa cell migration by inhibiting the phosphorylation of Girdin. The expression and production of vascular endothelial growth factor A (VEGF-A) was significantly decreased in Girdin-knockdown cell lines. Furthermore, in Matrigel tube formation assays performed using culture supernatant, the lumen-forming ability of vascular endothelial cells was also decreased in Girdin-knockdown cell lines. However, SCU treatment did not significantly alter the expression or production of VEGF-A. These results suggested that Girdin is involved in EGF signaling-mediated migration of PaCa cells, that SCU inhibits PaCa invasion by suppressing Girdin activity, and that Girdin is also involved in angiogenesis via an activation pathway different from the action site of SCU. Girdin may be a prognostic biomarker, and the development of a novel molecular-targeted drugs for Girdin may improve the prognosis of PaCa in the future.

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Enhanced CXCL12/CXCR4 signaling increases tumor progression in radiation‑resistant pancreatic cancer

Cited by 11 publications

References 57 publications

Upregulation of integrin‑linked kinase enhances tumor progression in gemcitabine‑resistant pancreatic cancer

Upregulation of integrin‑linked kinase enhances tumor progression in gemcitabine‑resistant pancreatic cancer

SDF-1 expression and tumor-infiltrating lymphocytes identify clinical subtypes of triple-negative breast cancer with different responses to neoadjuvant chemotherapy and survival

Girdin regulates both migration and angiogenesis in pancreatic cancer cell lines

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