Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer

Li, Yanjing; He, Yiping; Butler, Wayne M.; Xu, Lingfan; Chang, Yan; Lei, Kefeng; Zhang, Hong; Zhou, Yinglu; Gao, Allen C.; Zhang, Qingfu; Taylor, Daniel; Cheng, Donghui; Farber-Katz, Suzette; Karam, Rachid; Landrith, Tyler; Li, Bing; Wu, Sitao; Hsuan, Vickie; Yang, Qing; Hu, Hailiang; Chen, Xufeng; Flowers, M.A.; McCall, Shannon J.; Lee, John K.; Smith, Bryan; Park, Jung Wook; Goldstein, Andrew S.; Witte, Owen N.; Wang, Qianben; Rettig, Matthew B.; Armstrong, Andrew J.; Cheng, Qing; Huang, Jiaoti

doi:10.1126/scitranslmed.aax0428

Cited by 70 publications

(45 citation statements)

References 33 publications

(48 reference statements)

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“…A successful example of such a strategy was recently published by our group showing that selectively targeting NE cells using navarixin, a CXCR2 inhibitor, can suppress the growth of PCa cells both in vitro and in xenograft models. 60 …”

Section: Origin and Biological Function Of Neuroendocrine Cellsmentioning

confidence: 99%

“… 74 It has also been shown that CXCR2 overexpression in LNCaP cells drives a neuroendocrine phenotype, and this may be a result of up-regulated PI3K/AKT, MAPK, and VEGFR signaling pathways. 60 Further studies are needed to fully understand the important role of CXCR2 in altering intracellular signaling for the emergence of NE phenotype.…”

Section: Molecular Mechanisms Of Neuroendocrine Differentiation In Prostate Cancermentioning

confidence: 99%

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Neuroendocrine cells of the prostate: Histology, biological functions, and molecular mechanisms

Butler

Huang

2021

Precision Clinical Medicine

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Prostate Cancer (PCa) is a common cause of cancer-related mortality in men worldwide. Although most men are diagnosed with low grade, indolent tumors that are potentially curable, a significant subset develops advanced disease where hormone therapy is required to target the androgen receptor (AR). Despite its initial effect, hormone therapy eventually fails and the tumor progresses to lethal stages despite continued inhibition of AR. This review article focuses on the role of PCa cellular heterogeneity in therapy resistance and disease progression. Although AR-positive luminal-type cells represent the vast majority of PCa cells, there exists a minor component of AR-negative neuroendocrine (NE) cells that are resistant to hormonal therapy and are enriched by the treatment. In addition, it is now well accepted that a significant subset of hormonally treated tumors recur as small cell neuroendocrine carcinoma (SCNC), further highlighting the importance of targeting NE cells in addition to the more abundant luminal-type cancer cells. Although it has been long recognized that NE cells are present in PCa, their underlying function in benign prostate and molecular mechanisms contributing to PCa progression remains poorly understood. In this article, we review the morphology and function of NE cells in benign prostate and PCa as well as underlying molecular mechanisms. In addition, we review the major reported mechanisms for transformation from common adenocarcinoma histology to the highly lethal SCNC, a significant clinical challenge in the management of advanced PCa.

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Section: Origin and Biological Function Of Neuroendocrine Cellsmentioning

confidence: 99%

Section: Molecular Mechanisms Of Neuroendocrine Differentiation In Prostate Cancermentioning

confidence: 99%

Neuroendocrine cells of the prostate: Histology, biological functions, and molecular mechanisms

Butler

Huang

2021

Precision Clinical Medicine

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“…In small cell prostate cancer, for instance, NE cells are highly metastatic and resistant to treatment [ 227 ]. In a recent study, Li et al [ 154 ] reported how CXCR2 expression is associated with prostate cancer progression and tumor grade and described how its blockade may serve as a viable approach to overcome the challenges of treating advanced therapy-resistant and metastatic prostate cancers. The study further revealed NE cells as being positive for CXCR2 and CXCL8 expression and alluded to their involvement in EM remodeling, angiogenesis, and invasion.…”

Section: Cytokines Involved In Prostate Cancer Metastasismentioning

confidence: 99%

“…The study further revealed NE cells as being positive for CXCR2 and CXCL8 expression and alluded to their involvement in EM remodeling, angiogenesis, and invasion. NE phenotype causes cellular switch to a form that exhibits high enrichment for gene sets of EMT, tumorigenesis, angiogenesis, and stem cell markers [ 154 ].…”

Section: Cytokines Involved In Prostate Cancer Metastasismentioning

confidence: 99%

Cytokines and Chemokines as Mediators of Prostate Cancer Metastasis

Adekoya

Richardson

2020

IJMS

111

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The consequences of prostate cancer metastasis remain severe, with huge impact on the mortality and overall quality of life of affected patients. Despite the convoluted interplay and cross talk between various cell types and secreted factors in the metastatic process, cytokine and chemokines, along with their receptors and signaling axis, constitute important factors that help drive the sequence of events that lead to metastasis of prostate cancer. These proteins are involved in extracellular matrix remodeling, epithelial-mesenchymal-transition, angiogenesis, tumor invasion, premetastatic niche creation, extravasation, re-establishment of tumor cells in secondary organs as well as the remodeling of the metastatic tumor microenvironment. This review presents an overview of the main cytokines/chemokines, including IL-6, CXCL12, TGFβ, CXCL8, VEGF, RANKL, CCL2, CX3CL1, IL-1, IL-7, CXCL1, and CXCL16, that exert modulatory roles in prostate cancer metastasis. We also provide extensive description of their aberrant expression patterns in both advanced disease states and metastatic sites, as well as their functional involvement in the various stages of the prostate cancer metastatic process.

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“…Therefore, it is necessary to research new therapeutic targets to overcome TKI resistance in patients with CML. C-X-C chemokine receptor 2 (CXCR2) is G-protein-coupled receptor that is overexpressed in various solid cancer types, including breast (16), gastric (17), colon (18), melanoma (19), ovarian (20), pancreatic (21), and prostate (22) cancers. Interleukin 8 (IL-8), a CXCR2 ligand, is highly associated with cellular stemness and drug resistance by inhibition of drug-induced apoptosis in resistant cells (23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

CXCR2 As a Novel Target for Overcoming Resistance to Tyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia Cells

Kim

Lee

Kang

et al. 2021

Preprint

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Background: Chronic myeloid leukemia (CML) is a reciprocal translocation disorder driven by a breakpoint cluster region (BCR)-Abelson leukemia virus (ABL) fusion gene that stimulates abnormal tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) are effective in the treatment of Philadelphia chromosome (Ph)+ CML patients. However, the appearance of TKI-resistant CML cells is a hurdle in CML treatment. Therefore, it is necessary to identify novel treatments that could target a different mechanism than that of tyrosine kinases.Methods: The study was designed to verify whether C-X-C chemokine receptor 2 (CXCR2) could be a novel target for TKI-resistant CML treatment. We examined CXCR2 ligands from CML patient samples and TKI-resistant CML cell lines. Then, we inhibited CXCR2 and examined the effects on cell proliferation and apoptosis using immunoblotting and flow cytometry. The CXCR2 inhibition effect was also confirmed using a mouse xenograft model with TKI-sensitive and -resistant CML cells.Results: Interleukin 8 (IL-8), a CXCR2 ligand, was significantly increased in the bone marrow serum of initially diagnosed CML patients. CML cell lines expressed CXCR2, regardless of their sensitivity to TKIs. IL-8 stimulated CXCR2, mTOR, and c-Myc mRNA expression in CML cell lines. CXCR2 antagonists suppressed the proliferation of CML cells via cell cycle arrest in the G2/M phase. In addition, CXCR2 inhibition attenuated mTOR, c-Myc, and BCR-ABL expression, leading to CML cell apoptosis, irrespective of TKI responsiveness. Moreover, SB225002, a CXCR2 antagonist, caused higher cell death in CML cells than TKIs. Using a mouse xenograft model, we confirmed that SB225002 suppresses CML cells, with a prominent effect on TKI-resistant CML cells.Conclusions: Taken together, our findings demonstrate that IL-8 is a prognostic factor to the progress of CML. Inhibiting the CXCR2-mTOR-c-Myc cascade is a promising therapeutic strategy to overcome TKI-sensitive and -insensitive CML. Thus, CXCR2 blockade is a novel therapeutic strategy to treat CML, and SB225002, a commercially available CXCR2 antagonist, might be a drug candidate to treat TKI-resistant CML.

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Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer

Cited by 70 publications

References 33 publications

Neuroendocrine cells of the prostate: Histology, biological functions, and molecular mechanisms

Neuroendocrine cells of the prostate: Histology, biological functions, and molecular mechanisms

Cytokines and Chemokines as Mediators of Prostate Cancer Metastasis

CXCR2 As a Novel Target for Overcoming Resistance to Tyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia Cells

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