Self-seeding circulating tumor cells promote the proliferation and metastasis of human osteosarcoma by upregulating interleukin-8

Liu, Tao; Ma, Qiang; Zhang, Yinglong; Wang, Xin; Xu, Kui; Kang, Yan; Dong, Wengang; Fan, Qingyu; Zhang, Yingqi; Qiu, Xiuchun

doi:10.1038/s41419-019-1795-7

Cited by 31 publications

(18 citation statements)

References 40 publications

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“…Additionally, high VEGF and TGFβ expression have been associated with a poor prognosis among patients with osteosarcoma [ 41 , 42 ], and interruption of VEGF and TGFβ signaling was shown to disrupt osteosarcoma progression and metastasis [ 42 , 43 ]. Other soluble factors, such as IL-8 and ANGPTL2 have been additionally shown to mediate osteosarcoma metastatic progression and PMN formation in different mouse models [ 39 , 44 ]. These reports collectively provide evidence that tumor-secreted factors are also involved in osteosarcoma PMN formation, but further investigation is still required to help understand if they act in combination with EVs to establish a functional PMN.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Role of Osteosarcoma-Derived Extracellular Vesicles in Pre-Metastatic Niche Formation and Metastasis in the 143-B Xenograft Mouse Osteosarcoma Model

Mazumdar

Urdínez

Boro

et al. 2020

Cancers

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The pre-metastatic niche (PMN) is a tumor-driven microenvironment in distant organs that can foster and support the survival and growth of disseminated tumor cells. This facilitates the establishment of secondary lesions that eventually form overt metastasis, the main cause of cancer-related death. In recent years, tumor-derived extracellular-vesicles (EVs) have emerged as potentially key drivers of the PMN. The role of the PMN in osteosarcoma metastasis is poorly understood and the potential contribution of osteosarcoma cell-derived EVs to PMN formation has not been investigated so far. Here, we characterize pulmonary PMN development using the spontaneously metastasizing 143-B xenograft osteosarcoma mouse model. We demonstrate the accumulation of CD11b+ myeloid cells in the pre-metastatic lungs of tumor-bearing mice. We also establish that highly metastatic 143-B and poorly metastatic SAOS-2 osteosarcoma cell-derived EV education in naïve mice can recapitulate the recruitment of myeloid cells to the lungs. Surprisingly, despite EV-induced myeloid cell infiltration in the pre-metastatic lungs, 143-B and SAOS-2 EVs do not contribute towards the 143-B metastatic burden in the context of both spontaneous as well as experimental metastasis in severe-combined immunodeficient (SCID) mice. Taken together, OS-derived EVs alone may not be able to form a functional PMN, and may perhaps require a combination of tumor-secreted factors along with EVs to do so. Additionally, our study gives a valuable insight into the PMN complexity by providing the transcriptomic signature of the premetastatic lungs in an osteosarcoma xenograft model for the first time. In conclusion, identification of regulators of cellular and molecular changes in the pre-metastatic lungs might lead to the development of a combination therapies in the future that interrupt PMN formation and combat osteosarcoma metastasis.

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Section: Discussionmentioning

confidence: 99%

Exploring the Role of Osteosarcoma-Derived Extracellular Vesicles in Pre-Metastatic Niche Formation and Metastasis in the 143-B Xenograft Mouse Osteosarcoma Model

Mazumdar

Urdínez

Boro

et al. 2020

Cancers

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“…The prognostic and therapeutic implications of CTC phenotype detection based on cell size and EMT‐associated markers have been extensively reported in series of clinical cancer research (Aceto et al, 2014; Müller et al, 2014; Wan et al, 2017; Zhang et al, 2017). Although early‐stage CTC detection and improved adjuvant therapy for cancer patients have been largely achieved, yet potential defects in techniques are manifested in multiple respects and the current platforms are not sufficient for CTC screening in HD candidates (Keller & Pantel, 2019; Kim et al, 2009; Liu et al, 2019; Sorber et al, 2017; Zhang et al, 2019). Herein, on the basis of the ISET technique and size‐based platform, we conducted multidimensional modifications to satisfy the stricter standards for high‐efficient CTC identification and large‐scale application in general population.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, we recently reported the genome‑wide pattern differences in copy number variations (CNVs) of CTCs in breast cancer patients with liver metastasis (Zou et al, 2020). However, cytometric enumeration and genetic characteristics are extremely challenging due to the rare content, temporal−temporal variation, disseminated tumor heterogeneity, and the complexity of microenvironmental constituents in peripheral blood (Keller & Pantel, 2019; Kim et al, 2009; Liu et al, 2019; Sorber et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Multifaceted modifications for a cell size‐based circulating tumor cell scope technique hold the prospect for large‐scale application in general populations

Zhang

Zou

et al. 2020

Cell Biology International

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Circulating tumor cells (CTCs) indicate the diagnosis and prognosis of cancer patients, together with benefiting individual treatment and anticancer drug development. However, their large‐scale application in general population still requires systematically multifaceted modifications for currently proprietary new technologies based on filtration. We primitively utilized a cell size‐based platform to evaluate the recovery efficiency of spiked abnormal cell lines and analyzed circulating abnormal cells (CACs). To dissect the subpopulations of CACs, we conducted immunofluorescent (IF) staining with a combination of unique biomarkers of CTCs and circulating endothelial cells (CECs). Furthermore, we improved the CTC screening system by assessing the feasibility of transferring CTCs for automatic IF analysis, together with simulating and optimizing the circumstances for long‐term CTC storage and transportation. We detected CACs in 15 HD candidates with CTC characteristics such as abnormally large cytomorphology, high nuclear−cytoplasmic ratio, and positive for panCK or VIM staining. Thereafter, we improved accuracy of the platform by distinguishing CTCs from CECs, which satisfied the elementary requirement for small‐scale CTC screening in HD candidates. Finally, large‐scale CTC screening in general population was available after multifaceted modifications including automatic analysis by transferring CTCs on slides, choosing the appropriate blood‐collecting tube, optimizing the conditions for long‐term CTC storage and transportation, and evaluating the potential effect on the CTC phenotype. Hence, we systematically modified the scope of technique parameters, improved the accuracy of early cancer detection, and made it realizable for large‐scale CTC or CEC screening in general population.

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“…Serum-free MEM medium with SDF-1 (50 nM) was added to the bottom chamber. After incubation for 5 h, cells remained on the upper membrane were removed with a cotton swab, while cells that had migrated through the membrane were fixed in formaldehyde, stained with crystal violet and imaged using Zeiss AxioScope A1 microscope, the cell number was quantified using ImageJ software [ 36 ].…”

Section: Methodsmentioning

confidence: 99%

The negative charge of the 343 site is essential for maintaining physiological functions of CXCR4

Wang

Xiong

et al. 2021

BMC Mol and Cell Biol

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Background Warts, hypogammaglobulinemia, recurrent bacterial infections and myelokathexis (WHIM) syndrome is a primary immunodeficiency disease (PID) usually caused by autosomal dominant mutations in the chemokine receptor CXCR4 gene. To date, a total of nine different mutations including eight truncation mutations and one missense mutation (E343K, CXCR4E343K) distributed in the C-terminus of CXCR4 have been identified in humans. Studies have clarified that the loss of phosphorylation sites in the C-terminus of truncated CXCR4 impairs the desensitization process, enhances the activation of G-protein, prolongs downstream signaling pathways and introduces over immune responses, thereby causing WHIM syndrome. So far, there is only one reported case of WHIM syndrome with a missense mutation, CXCR4E343K, which has a full length of C-terminus with entire phosphorylation sites, no change in all potential phosphorylation sites. The mechanism of the missense mutation (CXCR4E343K) causing WHIM syndrome is unknown. This study aimed to characterize the effect of mutation at the 343 site of CXCR4 causing the replacement of arginine/E with glutamic acid/K on the receptor signal transduction, and elucidate the mechanism underling CXCR4E343K causing WHIM in the reported family. Results We completed a series of mutagenesis to generate different mutations at the 343 site of CXCR4 tail, and established a series of HeLa cell lines stably expressing CXCR4WT or CXCR4E343D (glutamic acid/E replaced with aspartic acid/D) or CXCR4E343K (glutamic acid/E replaced with lysine/K) or CXCR4E343R (glutamic acid/E replaced with arginine/R) or CXCR4E343A (glutamic acid/E replaced with alanine/A) and then systematically analyzed functions of the CXCR4 mutants above. Results showed that the cells overexpressing of CXCR4E343D had no functional changes with comparison that of wild type CXCR4. However, the cells overexpressing of CXCR4E343K or CXCR4E343R or CXCR4E343A had enhanced cell migration, prolonged the phosphorylation of ERK1/2, p38, JNK1/2/3, aggravated activation of PI3K/AKT/NF-κB signal pathway, introduced higher expression of TNFa and IL6, suggesting over immune response occurred in CXCR4 mutants with charge change at the 343 site of receptor tail, as a result, causing WHIM syndrome. Biochemical analysis of those mutations at the 343 site of CXCR4 above shows that CXCR4 mutants with no matter positive or neutral charge have aberrant signal pathways downstream of activated mutated CXCR4, only CXVR4 with negative charge residues at the site shows normal signal pathway post activation with stromal-derived factor (SDF1, also known as CXCL12). Conclusion Taken together, our results demonstrated that the negative charge at the 343 site of CXCR4 plays an essential role in regulating the down-stream signal transduction of CXCR4 for physiological events, and residue charge changes, no matter positive or neutral introduce aberrant activities and functions of CXCR4, thus consequently lead to WHIM syndrome.

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Self-seeding circulating tumor cells promote the proliferation and metastasis of human osteosarcoma by upregulating interleukin-8

Cited by 31 publications

References 40 publications

Exploring the Role of Osteosarcoma-Derived Extracellular Vesicles in Pre-Metastatic Niche Formation and Metastasis in the 143-B Xenograft Mouse Osteosarcoma Model

Exploring the Role of Osteosarcoma-Derived Extracellular Vesicles in Pre-Metastatic Niche Formation and Metastasis in the 143-B Xenograft Mouse Osteosarcoma Model

Multifaceted modifications for a cell size‐based circulating tumor cell scope technique hold the prospect for large‐scale application in general populations

The negative charge of the 343 site is essential for maintaining physiological functions of CXCR4

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