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 9 publications

(4 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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“…Moreover, they found that CXCR4 expression and invasion were enhanced in radiation-resistant pancreatic cancer cell lines compared to normal cancer cell lines. The CXCR4 antagonist AMD070 suppressed the cancer cell invasion enhanced by CXCL12 treatment, and when used in combination with irradiation, AMD070 suppressed the colonization of radiation-resistant pancreatic cancer cells ( 117 ). Alternatively, CXCR4-CXCL12 axis can be inhibited by directly preventing CXCL12 binding to CXCR4 or CXCR7.…”

Section: Critical Analysismentioning

confidence: 99%

The role of CXCL12 axis in pancreatic cancer: New biomarkers and potential targets

et al. 2023

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IntroductionChemokines are small, secreted peptides involved in the mediation of the immune cell recruitment. Chemokines have been implicated in several diseases including autoimmune diseases, viral infections and also played a critical role in the genesis and development of several malignant tumors. CXCL12 is a homeostatic CXC chemokine involved in the process of proliferation, and tumor spread. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors, that is still lacking effective therapies and with a dramatically poor prognosis.MethodWe conducted a scientific literature search on Pubmed and Google Scholar including retrospective, prospective studies and reviews focused on the current research elucidating the emerging role of CXCL12 and its receptors CXCR4 – CXCR7 in the pathogenesis of pancreatic cancer.ResultsConsidering the mechanism of immunomodulation of the CXCL12-CXCR4-CXCR7 axis, as well as the potential interaction with the microenvironment in the PDAC, several combined therapeutic approaches have been studied and developed, to overcome the “cold” immunological setting of PDAC, like combining CXCL12 axis inhibitors with anti PD-1/PDL1 drugs.ConclusionUnderstanding the role of this chemokine’s axis in disease initiation and progression may provide the basis for developing new potential biomarkers as well as therapeutic targets for related pancreatic cancers.

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

Cited by 9 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

The role of CXCL12 axis in pancreatic cancer: New biomarkers and potential targets

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