Cancer Cells Enter an Adaptive Persistence to Survive Radiotherapy and Repopulate Tumor

Zhao, Yucui; Lü, Tingting; Song, Yanwei; Wen, Yanqin; Deng, Zheng; Fan, Jiahui; Zhao, Minghui; Zhao, Ruyi; Luo, Yu; Xie, Jianzhu; Hu, Binjie; Sun, Haoran; Wang, Yiwei; He, Sijia; Gong, Yanping; Cheng, Jin; Liu, Xinjian; Yu, Liang; Li, Jikun; Li, Chuan-Yuan; Shi, Yongyong; Huang, Qian

doi:10.1002/advs.202204177

Cited by 14 publications

(14 citation statements)

References 81 publications

(56 reference statements)

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“…Moreover, CysC may be conducive to tumor cell invasion and angiogenesis by protecting matrix metalloproteinase-9 from autolysis ( Mira et al, 2004 ; Paupert et al, 2008 ). Zhao et al also reported that elevated expression of CST3, the gene encoding cystatin C, was critical for cellular polyploidization that may facilitate cancer cells to resist radiation therapy ( Zhao et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Associations of serum cystatin C concentrations with total mortality and mortality of 12 site-specific cancers

Huang,

Lu,

Yang

et al. 2024

Front. Mol. Biosci.

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Purpose:Cystatin C (CysC), beyond its biomarker role of renal function, has been implicated in various physical and pathological activities. However, the impact of serum CysC on cancer mortality in a general population remains unknown. We aimed to examine the associations of serum CysC concentrations with total mortality and mortality of 12 site-specific cancers.Methods:We included 241,008 participants of the UK Biobank cohort with CysC measurements who had normal creatinine-based estimated glomerular filtration rates and were free of cancer and renal diseases at baseline (2006–2010). Death information was obtained from the National Health Service death records through 28 February 2021. Multivariable Cox proportional hazards models were used to compute hazard ratios (HR) per one standard deviation increase in log-transformed CysC concentrations and 95% confidence intervals (95% CI) for mortality.Results:Over a median follow-up of 12.1 (interquartile range, 11.3–12.8) years, 5,744 cancer deaths occurred. We observed a positive association between serum CysC concentrations and total cancer mortality (HR = 1.16, 95% CI: 1.12–1.20). Specifically, participants with higher serum CysC concentrations had increased mortality due to lung cancer (HR = 1.12, 95% CI: 1.05–1.20), blood cancer (HR = 1.29, 95% CI: 1.16–1.44), brain cancer (HR = 1.19, 95% CI: 1.04–1.36), esophageal cancer (HR = 1.20, 95% CI: 1.05–1.37), breast cancer (HR = 1.18, 95% CI: 1.03–1.36), and liver cancer (HR = 1.49, 95% CI: 1.31–1.69).Conclusion:Our findings indicate that higher CysC concentrations are associated with increased mortality due to lung, blood, brain, esophageal, breast, and liver cancers. Future studies are necessary to clarify underlying mechanisms.

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Section: Discussionmentioning

confidence: 99%

Associations of serum cystatin C concentrations with total mortality and mortality of 12 site-specific cancers

Huang,

Lu,

Yang

et al. 2024

Front. Mol. Biosci.

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“…In our study, RD cells were used to establish ectopic (41)(42)(43) and orthotopic (44) xenografts. Importantly, previous chemotherapy and radiotherapy may lead to multiple changes in tumor biology, which is different from the biology of the primary tumor including genetic mutations and alterations in the DNA and changes in tumor heterogeneity (45,46). GEMM models of RMS were infrequently utilized (n = 10), which may be attributed to their technical complexity, long development times, and high cost.…”

Section: Discussionmentioning

confidence: 99%

Contemporary preclinical mouse models for pediatric rhabdomyosarcoma: from bedside to bench to bedside

Martynov,

Dhaka,

Wilke

et al. 2024

Front. Oncol.

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BackgroundRhabdomyosarcoma (RMS) is the most common pediatric soft-tissue malignancy, characterized by high clinicalopathological and molecular heterogeneity. Preclinical in vivo models are essential for advancing our understanding of RMS oncobiology and developing novel treatment strategies. However, the diversity of scholarly data on preclinical RMS studies may challenge scientists and clinicians. Hence, we performed a systematic literature survey of contemporary RMS mouse models to characterize their phenotypes and assess their translational relevance.MethodsWe identified papers published between 01/07/2018 and 01/07/2023 by searching PubMed and Web of Science databases.ResultsOut of 713 records screened, 118 studies (26.9%) were included in the qualitative synthesis. Cell line-derived xenografts (CDX) were the most commonly utilized (n = 75, 63.6%), followed by patient-derived xenografts (PDX) and syngeneic models, each accounting for 11.9% (n = 14), and genetically engineered mouse models (GEMM) (n = 7, 5.9%). Combinations of different model categories were reported in 5.9% (n = 7) of studies. One study employed a virus-induced RMS model. Overall, 40.0% (n = 30) of the studies utilizing CDX models established alveolar RMS (aRMS), while 38.7% (n = 29) were embryonal phenotypes (eRMS). There were 20.0% (n = 15) of studies that involved a combination of both aRMS and eRMS subtypes. In one study (1.3%), the RMS phenotype was spindle cell/sclerosing. Subcutaneous xenografts (n = 66, 55.9%) were more frequently used compared to orthotopic models (n = 29, 24.6%). Notably, none of the employed cell lines were derived from primary untreated tumors. Only a minority of studies investigated disseminated RMS phenotypes (n = 16, 13.6%). The utilization areas of RMS models included testing drugs (n = 64, 54.2%), studying tumorigenesis (n = 56, 47.5%), tumor modeling (n = 19, 16.1%), imaging (n = 9, 7.6%), radiotherapy (n = 6, 5.1%), long-term effects related to radiotherapy (n = 3, 2.5%), and investigating biomarkers (n = 1, 0.8%). Notably, no preclinical studies focused on surgery.ConclusionsThis up-to-date review highlights the need for mouse models with dissemination phenotypes and cell lines from primary untreated tumors. Furthermore, efforts should be directed towards underexplored areas such as surgery, radiotherapy, and biomarkers.

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“…formed in the absence of TME or immune cell reaction, and based on the alternating mechanism of reversible poly- and de-polyploidization mechanism to survive radiotherapy was reported by Zhao et al [ 35 ]. It is also important that a few of specific regulatory chains may modulate relationships between separate tumor cell sub-groups, and anaplastic lymphoma kinase is a protein able to make colon cancer cells to form populations with the enhanced recurrence potential [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex

Sverchinsky,

Alhasan,

Mikeladze

et al. 2023

J Exp Clin Cancer Res

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Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence.

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Cancer Cells Enter an Adaptive Persistence to Survive Radiotherapy and Repopulate Tumor

Cited by 14 publications

References 81 publications

Associations of serum cystatin C concentrations with total mortality and mortality of 12 site-specific cancers

Associations of serum cystatin C concentrations with total mortality and mortality of 12 site-specific cancers

Contemporary preclinical mouse models for pediatric rhabdomyosarcoma: from bedside to bench to bedside

Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex

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