CC Chemokine Ligand-2: A Promising Target for Overcoming Anticancer Drug Resistance

Shi, Zhenbo; Tu, Jian; Ying, Ying; Diao, Yunlian; Zhang, Ping; Liao, Shu-Yuan; Xiong, Zhijuan; Huang, Shibo

doi:10.3390/cancers14174251

Cited by 7 publications

(11 citation statements)

References 98 publications

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“…Our study found a distinct mechanism that GAF was an extraneous factor promoting continuous ERK1/2 activation in GBM cells. Moreover, CCL2 secreted by GAFs induced chemoresistance of GBM cells through MEK1/2-ERK1/2 signaling activation, rather than previously reported CCL2-mediated PI3K/AKT activation 26 . We also successfully validated our findings of the relationship between GAFs and chemoresistance of GBMs by ex vivo GBO models, which encouraged us to take advantage of the patient-derived organoids to assess the chemoresistance-promoting role of GAFs in GBMs and conduct preclinical investigations to target GAF-GBM interplay.…”

Section: Discussioncontrasting

confidence: 77%

“…Among cytokine-encoding genes cataloged in the Cytokine Registry (https://www.immport.org/resources/cytokineRegistry), CCL2 expressed at a significantly higher level in the GAFs compared to GBM cells (Figure 4A). Recently, accumulating evidence suggested that CCL2 not only mediated chemotaxis of several immune cells but also could induce multiple solid tumors resistant to a broad spectrum of anticancer drugs [26][27][28] . Correlation analysis showed that GAF was positively associated with the expression level of CCL2 in both IDH-wildtype and IDH-mutant gliomas (Figures 4B and S4A).…”

Section: Gafs Promote Tmz Resistance Of Gbm Cells By Preferentially S...mentioning

confidence: 99%

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Glioma-associated fibroblasts promote glioblastoma resistance to temozolomide through CCL2-CCR2 paracrine signaling

Zuo,

Zhang,

Chen

et al. 2024

Preprint

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Complicated tumor microenvironment contributes mostly to chemoresistance in glioblastoma. Glioma-associated fibroblasts (GAFs) were recently identified as non-tumor stromal cells in the glioblastoma microenvironment, whereas their function in glioblastoma chemoresistance is unclear. Herein, we interrogated the correlation between GAFs and chemoresistance of glioblastoma by examining a series of patient-derived GAFs and glioblastoma organoids (GBOs), revealing that GAFs could promote temozolomide resistance in glioblastoma. Mechanistically, C-C motif chemokine ligand 2 (CCL2) secreted by GAFs selectively activated the ERK1/2 signaling in glioblastoma cells to potentiate temozolomide resistance. Pharmacologically disrupting the CCL2-CCR2 axis or MEK1/2-ERK1/2 pathway effectively improved the therapeutic efficacy of temozolomide in GBM cells and patient-derived GBOs, and both decreased phospho-ERK1/2 expression. Collectively, our results identified that targeting the GAF-dominated CCL2-ERK1/2 pathway may be an alternative strategy to alleviate the GAF-mediated chemoresistance of glioblastoma.

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Section: Discussioncontrasting

confidence: 77%

Section: Gafs Promote Tmz Resistance Of Gbm Cells By Preferentially S...mentioning

confidence: 99%

Glioma-associated fibroblasts promote glioblastoma resistance to temozolomide through CCL2-CCR2 paracrine signaling

Zuo,

Zhang,

Chen

et al. 2024

Preprint

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“…10A–D ). Previous studies have demonstrated that CCL2 can recruit MDSCs infiltration to form an immunosuppressive microenvironment, which helps tumor cells evade the attack of immune cells and supports tumor cell proliferation [ 26 ]. Since CCL2, as a secreted factor, plays a role in immune cell chemotaxis through the CCR2 receptor, we extracted the supernatants of cultured tumor cells for ELISA.…”

Section: Resultsmentioning

confidence: 99%

IFI35 limits antitumor immunity in triple-negative breast cancer via CCL2 secretion

Xu,

Sun,

Liu

et al. 2024

Oncogene

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Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis due to the lack of therapeutic targets. Although immunotherapy brings survival benefits to patients diagnosed with TNBC, it remains limited and treatment resistance is widespread. Here we demonstrate that IFI35 is highly expressed in tumor tissues and can be induced by Interferon-γ in a time-dependent and concentration-dependent manner in breast cancer cells. In xenograft models, we reveal that IFI35 dramatically increases myeloid-derived suppressor cells infiltration in tumors, along with depletion and anergy of CD8+T cells. IFI35 ablation leads to prolonged survival of the mice. Mechanistically, RNA-sequencing reveals that IFI35 promotes CCL2 secretion, resulting in the remodeling of TNBC immune microenvironment. Ablation of IFI35 promotes the infiltration of effector CD8+T cells, and thereby sensitizes TNBC to anti-PD-1 immunotherapy. Our data suggest that IFI35 limits antitumor immunity and may be expected to become a new immunotherapy target in TNBC.

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“…Notably, CCL2 was newly detected in the on-chip co-culture with vessels. CCL2 is known to support tumor development, migration and concurrently resists anti-cancer drugs by reducing sensitivity to drug and apoptosis [69][70][71]. More detailed results can be derived using the platform, yet, the importance of endothelium in drug resistance evaluation should be reconsidered.…”

Section: Direct Harvest Of On-chip Tumor Samples and Secretome/gene E...mentioning

confidence: 99%

3D vascularized microphysiological system for investigation of tumor-endothelial crosstalk in anti-cancer drug resistance

Kim,

Park,

et al. 2023

Biofabrication

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Despite the advantages of microfluidic system in drug screening, vascular systems responsible for the transport of drugs and nutrients have been hardly considered in the microfluidic-based chemotherapeutic screening. Considering the physiological characteristics of highly vascularized urinary tumors, we here investigated the chemotherapeutic response of bladder tumor cells using a vascularized tumor on a chip. The microfluidic chip was designed to have open-top region for tumor sample introduction and hydrophilic rail for spontaneous hydrogel patterning, which contributed to the construction of tumor-hydrogel-endothelium interfaces in a spatiotemporal on-demand manner. Utilizing the chip where intravascularly injected cisplatin diffuse across the endothelium and transport into tumor samples, chemotherapeutic responses of cisplatin-resistant or -susceptible bladder tumor cells were evaluated, showing the preservation of cellular drug resistance even within the chip. The open-top structure also enabled the direct harvest of tumor samples and post analysis in terms of secretome and gene expressions. Comparing the cisplatin efficacy to the cisplatin-resistant tumor cells in the presence or absence of endothelium, we found that the proliferation rates of tumor cells were increased in the vasculature-incorporated chip. These have suggested that our vascularized tumor chip allows establishment of vascular-gel-tumor interfaces in spatiotemporal manners and further enables investigations of chemotherapeutic screening.

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CC Chemokine Ligand-2: A Promising Target for Overcoming Anticancer Drug Resistance

Cited by 7 publications

References 98 publications

Glioma-associated fibroblasts promote glioblastoma resistance to temozolomide through CCL2-CCR2 paracrine signaling

Glioma-associated fibroblasts promote glioblastoma resistance to temozolomide through CCL2-CCR2 paracrine signaling

IFI35 limits antitumor immunity in triple-negative breast cancer via CCL2 secretion

3D vascularized microphysiological system for investigation of tumor-endothelial crosstalk in anti-cancer drug resistance

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