Κυριακή 22 Μαρτίου 2020

1.
 2020 Mar 5;10:300. doi: 10.3389/fonc.2020.00300. eCollection 2020.

The Combination Options and Predictive Biomarkers of PD-1/PD-L1 Inhibitors in Esophageal Cancer.

Yang H1Wang K1Wang T1Li M1Li B1Li S1Yuan L1.

Abstract

Esophageal cancer (EC) is one of the most common cancers with poor survival in the world. Nowadays, a generous number of clinical trials are underway on the use of immunotherapy in EC patients, especially the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors. However, only a few patients could benefit from single-agent therapy. Others need combination therapies to enhance the response rate and survival. In this review, we focus on PD-1/PD-L1 inhibitors and its combination options in EC patients. We also summarized the potential predictive biomarkers for PD-1/PD-L1 inhibitors treatment.

KEYWORDS:

combination therapy; esophageal cancer; predictive biomarkers; programmed death-1; programmed death-ligand 1
2.
 2020 Mar 4;10:298. doi: 10.3389/fonc.2020.00298. eCollection 2020.

Management of Cancer Cachexia: Attempting to Develop New Pharmacological Agents for New Effective Therapeutic Options.

Abstract

Cancer cachexia (CC) is a multifactorial syndrome characterized by systemic inflammation, uncontrolled weight loss and dramatic metabolic alterations. This includes myofibrillar protein breakdown, increased lipolysis, insulin resistance, elevated energy expediture, and reduced food intake, hence impairing the patient's response to anti-cancer therapies and quality of life. While a decade ago the syndrome was considered incurable, over the most recent years much efforts have been put into the study of such disease, leading to the development of potential therapeutic strategies. Several important improvements have been reached in the management of CC from both the diagnostic-prognostic and the pharmacological viewpoint. However, given the heterogeneity of the disease, it is impossible to rely only on single variables to properly treat patients presenting this metabolic syndrome. Moreover, the cachexia symptoms are strictly dependent on the type of tumor, stage and the specific patient's response to cancer therapy. Thus, the attempt to translate experimentally effective therapies into the clinical practice results in a great challenge. For this reason, it is of crucial importance to further improve our understanding on the interplay of molecular mechanisms implicated in the onset and progression of CC, giving the opportunity to develop new effective, safe pharmacological treatments. In this review we outline the recent knowledge regarding cachexia mediators and pathways involved in skeletal muscle (SM) and adipose tissue (AT) loss, mainly from the experimental cachexia standpoint, then retracing the unimodal treatment options that have been developed to the present day.

KEYWORDS:

animal models; cachexia mediators; cancer cachexia; clinical trials; muscle tissue and adipose tissue loss; therapeutic strategies
3.
 2020 Mar 5;10:297. doi: 10.3389/fonc.2020.00297. eCollection 2020.

Ultimate Functional Preservation With Intersphincteric Resection for Rectal Cancer.

Abstract

The proximity of the very low rectum rectal cancer to the anal sphincter raises a specific problem: how and until when can we preserve the anal continence without compromising the oncological result of the tumor resection? In this situation, intersphincteric resection (ISR) offers an excellent alternative to abdominoperineal resection (APR), but the selection of patients for this option must be extremely precise. This complex choice justifies the simultaneous consideration of an oncological approach with a functional approach in order to provide a full benefit to the patient. When a circumferential resection margin of at least 1 mm can be performed with a distal resection margin of at least 1 cm with or without preoperative radiotherapy, ISR ensures a safety choice. The oncological results of ISR reported in the literature when performed properly found a 5-year disease-free survival of 80.2% with a local recurrence rate of only 5.8%. In parallel to this oncological evaluation, the expected post-operative functional outcome and the resulting quality of life must be properly assessed pre-operatively, since partial or total resection of the internal sphincter impacts significantly on the functional outcome. Based on data from the literature, this work reports the essential anatomical considerations and then the oncological and functional elements indispensables when an anal continence preservation is evoked for a tumor of the very low rectum. Finally, the precise selection criteria and the major surgical principles are outlined in order to guarantee the safety of this modern choice for the patient.

KEYWORDS:

LARS—low anterior resection syndrome; functional results; intersphincteric resection (ISR); neoadjucant chemoradiation; rectal cancer
4.
 2020 Mar 5;10:296. doi: 10.3389/fonc.2020.00296. eCollection 2020.

Increased HDAC Activity and c-MYC Expression Mediate Acquired Resistance to WEE1 Inhibition in Acute Leukemia.

Abstract

WEE1 is a cell cycle and DNA damage response kinase that is emerging as a therapeutic target for cancer. AZD1775 is a small molecule inhibitor of WEE1, currently in early phase clinical trials as a single agent and in combination with more conventional anti-neoplastic agents. As resistance to kinase inhibitors is frequent, we sought to identify mechanisms of resistance to WEE1 inhibition in acute leukemia. We found that AZD1775 resistant cell lines are dependent upon increased HDAC activity for their survival, in part due to increased KDM5A activity. In addition, gene expression analyses demonstrate HDAC dependent increase in MYC expression and c-MYC activity in AZD1775 treated resistant cells. Overexpression of c-MYC confers resistance to AZD1775 in cell lines with low baseline expression. Pharmacologic inhibition of BRD4, and thereby c-MYC, partially abrogated resistance to AZD1775. Thus, acquired resistance to WEE1 inhibition may be reversed by HDAC or BRD4 inhibition in leukemia cells.

KEYWORDS:

AZD1775; KDM5A; WEE1; adavosertib; c-MYC; histone deacetylase
5.
 2020 Mar 5;10:291. doi: 10.3389/fonc.2020.00291. eCollection 2020.

Long Non-coding RNA MIR570MG Causes Regorafenib Resistance in Colon Cancer by Repressing miR-145/SMAD3 Signaling.

Wei F1Wang M1Li Z1Wang Y1Zhou Y1.

Abstract

An increasing number of studies have shown that long non-coding RNA (lncRNA) dysregulation plays a fundamental role in the development of various cancers, including colon cancer. Nonetheless, the mechanisms of lncRNA in regorafenib-resistance remain unclear. Our research revealed the lncRNA MIR570MG increased in regorafenib-resistant colon cancer cells compared to the regorafenib-sensitive cells. Furthermore, MIR570MG sponged miR-145, which declined in regorafenib-resistant colon cancer cell lines. More importantly, overexpression of miR-145 hampered cell proliferation and retrieved colon cancer regorafenib-sensitivity, contrary to the function of MIR570MG. Dual-luciferase reporter assay confirmed that miR-145 bound to 3'-UTR of SMAD3, a transcriptional modulator activated by TGFβ, resulting in blockage of TGFβ /SMAD3-mediated cell growth and cycle progression. Besides, ectopic expression of miR-145 inhibitor in the parental cells endowed resistance to regorafenib. Inversely, knockdown of MIR570MG impoverished resistance against regorafenib. Additionally, overexpression of MIR570MG conquered the suppression of tumor growth by miR-146 and rehabilitated the resistance to regorafenib in HCT116R human colon cancer mouse models. In summary, our findings suggested that MIR570MG promoted regorafenib resistance via releasing SMAD3 from miR-145, leading to activation of SMAD3-mediated signaling pathways.

KEYWORDS:

LncRNA MIR570MG; SMAD3; TGFβ; metastatic colon cancer; miR-145; regorafenib; resistance
6.
 2020 Mar 3;10:290. doi: 10.3389/fonc.2020.00290. eCollection 2020.

Diagnostic Accuracy of Droplet Digital PCR and Amplification Refractory Mutation System PCR for Detecting EGFR Mutation in Cell-Free DNA of Lung Cancer: A Meta-Analysis.

Li C1He Q1Liang H1Cheng B1Li J1Xiong S1Zhao Y1Guo M1Liu Z1He J1Liang W1.

Abstract

Background: Epidermal growth factor receptor (EGFR) mutation testing in plasma cell-free DNA (cfDNA) from advanced lung cancer patients is an emerging clinical tool. This meta-analysis was designed to determine the diagnostic accuracy of two common PCR systems, droplet digital PCR (ddPCR) and amplification refractory mutation system PCR (ARMS-PCR), for detecting EGFR mutation in cfDNA. Materials and methods: A systematic search was carried out based on PubMed, Web of science, Embase and the Cochrane library. Data from eligible studies were extracted and pooled to calculate the sensitivity, specificity, diagnostic odds ratio (DOR), area under the summary receiver-operating characteristic curve (AUROC), using tissue biopsy results as the standard method. Subgroup analyses were performed regarding EGFR mutation type, tumor stage, and EGFR-TKI treatment. Results: Twenty-five studies involving 4,881 cases were included. The plasma testing sensitivity, specificity, DOR, and AUROC, compared with the matched tumor tissues, were 72.1%, 95.6%, 38.5, 0.89 for ddPCR, and 65.3%, 98.2%, 52.8, 0.71 for ARMS-PCR, respectively, through indirect comparison, significant differences were found in sensitivity (P = 0.003) and specificity (P = 0.007). Furthermore, significant difference was found in sensitivity between tumor stage subgroups (IIIB-IV subgroup vs. IA-IV subgroup) in ARMS-PCR (73.7 vs. 64.2%, P = 0.008), but not in ddPCR (72.5 vs. 71.2%, P = 0.756). Conclusions: This study demonstrates that ddPCR and ARMS-PCR have a high specificity with a practical sensitivity for detecting EGFR mutation in cfDNA, which supports their application as a supplement or a conditional-alternative to tissue biopsy in clinical practice for genotyping. It seems that ddPCR has a higher sensitivity than ARMS-PCR, especially in early stages.

KEYWORDS:

amplification refractory mutation system PCR (ARMS-PCR); cell free DNA (cfDNA); droplet digital PCR (ddPCR); epidermal growth factor receptor (EGFR); lung cancer
7.
 2020 Mar 3;10:287. doi: 10.3389/fonc.2020.00287. eCollection 2020.

A Fast Online Replanning Algorithm Based on Intensity Field Projection for Adaptive Radiotherapy.

Liu X1,2Liang Y3Zhu J4Yu G5Yu Y6Cao Q7Li XA8Li B2.

Abstract

Purpose: The purpose of this work was to propose an online replanning algorithm, named intensity field projection (IFP), that directly adjusts intensity distributions for each beam based on the deformation of structures. IFP can be implemented within a reasonably acceptable time frame. Methods and Materials: The online replanning method is based on the gradient-based free form deformation (GFFD) algorithm, which we have previously proposed. The method involves the following steps: The planning computed tomography (CT) and cone-beam CT image are registered to generate a three-dimensional (3-D) deformation field. According to the 3-D deformation field, the registered image and a new delineation are generated. The two-dimensional (2-D) deformation field of ray intensity in each beam direction is determined based on the 3-D deformation field in the region of interest. The 2-D ray intensity distribution in the corresponding beam direction is deformed to generate a new 2-D ray intensity distribution. According to the new 2-D ray intensity distribution, corresponding multi-leaf collimator (MLC), and jaw motion data are generated. The feasibility and advantages of our method have been demonstrated in 20 lung cancer intensity modulated radiation therapy (IMRT) cases. Results: Substantial underdosing in the CTV is seen in the original and the repositioning plans. The average prescription dose coverage (V100%) and D95 for CTV were 100% and 60.3 Gy for the IFP plans compared to 82.6% (P < 0.01) and 44.0 Gy (P < 0.01) for original plans, 86.7% (P < 0.01), and 58.5 Gy (P < 0.01) for repositioning plans. On average, the mean total lung doses were 12.2 Gy for the IFP plan compared to the 12.4 Gy (P < 0.01) and 12.6 Gy (P < 0.01) for the original and the repositioning plans. The entire process of IFP can be completed within 3 min. Conclusions: We proposed an online replanning strategy for automatically correcting interfractional anatomy variations. The preliminary results indicate that the IFP method substantially increased planning speed for online adaptive replanning.

KEYWORDS:

adaptive radiotherapy; deformable image registration; image guided radiotherapy; interfractional variations; online replanning
8.
 2020 Mar 3;10:277. doi: 10.3389/fonc.2020.00277. eCollection 2020.

Corrigendum: Non-coding RNAs: Emerging Regulators of Sorafenib Resistance in Hepatocellular Carcinoma.

Abstract

[This corrects the article DOI: 10.3389/fonc.2019.01156.].

KEYWORDS:

hepatocellular carcinoma (HCC); long non-coding RNAs (lncRNAs); microRNAs (miRNAs); non-coding RNAs (ncRNAs); sorafenib resistance
9.
 2020 Mar 3;10:271. doi: 10.3389/fonc.2020.00271. eCollection 2020.

Real-World Data of Triplet Combination of Trastuzumab, Lapatinib, and Chemotherapy in HER2-Positive Metastatic Breast Cancer: A Multicenter Retrospective Study.

Li Y1Gong C1Lu Q2Zhou Z3Luo T4Li W5Li G6Ge R7Xu F2Wang B1.

Abstract

Introduction: Combination of trastuzumab (T) and lapatinib (L) has been showed to significantly improve the prognosis of HER2+ heavily pretreated metastatic breast cancer (MBC). Whether TL combined chemotherapy (TLC) can further improve the efficacy in HER2+ MBC remains to be further studied. The aim of the study was to report the first real-world data of TLC in HER2+ MBC, including the efficacy, safety and treatment patterns. Methods: Patients with HER2+ MBC treated with TLC in 5 institutions of China from September 2013 to July 2019 were included. Progression free survival (PFS), objective response rate (ORR), overall survival (OS), toxicity profile and treatment pattern were reported. Results: A total of 285 patients were included. 88.8% were exposed to trastuzumab and 49.2% received 2 or more lines of systematic therapy before TLC previously. The most common chemotherapy regimens combined with TL were capecitabine (40.7%) and vinorelbine (21.4%) and almost 1/3 received maintenance treatment after TLC. Median PFS was 10.9 months while patients received TLC as first line treatment showed longest median PFS of 20.7 months. Patients pretreated with trastuzumab showed a median PFS of 10.2 months. In patients who pretreated with trastuzumab, the continuation of trastuzumab on the basis of standard lapatinib plus capecitabine had a median PFS of 11.3 months. TL combined with capecitabine or vinorelbine showed no significant difference in median PFS, though TL combined with capecitabine had numerically prolongation (11.4 vs. 8.5 months, p = 0.231). Patients had brain metastasis (BM) also showed a median PFS (intracranial and extracranial lesions considered) of 10.6 months. Lines of systematic metastatic treatment was an independent predictive factor of PFS. The median OS was not reached. Two hundred and seventy seven patients were included in ORR analysis. ORR was 42.6%. Toxicities of triplet combinations were tolerable and the most common grade 3 and 4 adverse events were neutropenia (16.8%). Conclusions: TLC demonstrated promising effects and tolerable safety in HER2+MBC, even in patients with BM, providing a theoretical basis for clinical practice. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT04001634.

KEYWORDS:

chemotherapy; human epidermal growth factor receptor 2 positive; lapatinib; metastatic breast cancer; trastuzumab
10.
 2020 Mar 5;10:265. doi: 10.3389/fonc.2020.00265. eCollection 2020.

Perplexing Role of P-Glycoprotein in Tumor Microenvironment.

Abstract

Development of multidrug resistance (MDR) still remains a major obstacle to the long-term success of cancer therapy. P-glycoprotein (P-gp) is a well-identified membrane transporter with capability to efflux drug molecules out of the cancer cell leading to reduced efficiency of chemotherapy. Cancer cells upregulate P-gp expression as an adaptive response to evade chemotherapy mediated cell death. While several P-gp inhibitors have been discovered by in silico and pre-clinical studies, very few have successfully passed all phases of the clinical trials. Studies show that application of P-gp inhibitors in cancer therapy regimen following development of MDR achieved limited beneficial outcomes. While, the non-specific substrate binding to P-gp has made the drug-design a challenge, a bigger perplexing challenge comes from its role in tumor immunology. Expression of P-gp was noted immune cell phenotypes with apparently antagonistic functionality. Both pro-tumor MΦ2-macrophages and, anti-tumor NK-cell and Th17/CD4+T cell subsets have shown enhanced expression of P-gp. While drug based inhibition of P-gp in pro-tumor immune cell phenotypes could promote tumor elimination, however, it would not be a rational choice to exert inhibition of P-gp on anti-tumor immune cell phenotypes. This mutually exclusive paradigm of P-gp functionality requires a more comprehensive and detailed understanding of its role in tumor microenvironment with active interplay of cancer and immune cells in the tumor mileu. In this review, we focus on the current understanding of the role of P-gp in cancer cells and immune cells and finally attempt to highlight some caveats in the current understanding of its role in comprehensive tumor microenvironment along with challenges in the development of P-gp inhibitors toward anti-cancer therapy.

KEYWORDS:

P-glycoprotein; cancer; chemotherapy; metastasis; tumor immunology
11.
 2020 Mar 5;10:249. doi: 10.3389/fonc.2020.00249. eCollection 2020.

B Cells as Prognostic Biomarker After Surgery for Colorectal Liver Metastases.

Abstract

Background: The aim of this study was to identify more accurate variables to improve prognostication of individual patients with colorectal liver metastases (CRLM). Clinicopathological characteristics only partly explain the large range in survival rates. Methods: MessengerRNA expression profiles of resected CRLM of two patient groups were analysed by mRNA sequencing: poor survivors (death from recurrent disease <30 months after surgery) and good survivors (no recurrent disease >60 months after surgery). Tumour and adjacent liver parenchyma samples were analysed. Results: MessengerRNA expression profiling of the tumour samples identified 77 genes that were differentially expressed between the two survival groups at a False Discovery Rate (FDR) <0.1. In the adjacent liver parenchyma samples only one gene, MTRNR2L1, showed significantly higher expression in the good survivors. Pathway analysis showed higher expression of immune-related and stroma-related genes in tumour samples from good survivors. Expression data was then validated by immunohistochemistry in two cohorts comprising a total of 125 patients. Immunohistochemical markers that showed to be associated with good survival in the total cohort were: high K/L+ infiltration in tumour stroma [p = 0.029; OR 2.500 (95% CI 1.100-5.682)] and high CD79A+ infiltration in tumour stroma [p = 0.036; OR 2.428 (95%CI 1.062-5.552)]. Conclusions: A high stromal infiltration of CD79A+ B cells and K/L+ plasma cells might be favourable prognostic biomarkers after surgery for CRLM.

KEYWORDS:

B cells; RNA sequencing; cancer; colorectal liver metastases; genetics; immunohistochemistry
12.
 2020 Mar 5;10:240. doi: 10.3389/fonc.2020.00240. eCollection 2020.

Commentary: Predictors of Colorectal Cancer Screening in Two Underserved U.S. Populations: A Parallel Analysis.

KEYWORDS:

colon cancer incidence; colon incidence hotspots; gut micobiome; interdiscipinarity; spatial cancer
13.
 2020 Mar 4;10:237. doi: 10.3389/fonc.2020.00237. eCollection 2020.

Identification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant Chemotherapy.

Sahni S1,2,3Nahm C1,2,3Krisp C4Molloy MP1,5,6Mehta S1,2,3Maloney S1,2Itchins M1,2,7,8Pavlakis N1,2,7,8Clarke S1,2,7,8Chan D1,2,7,8Gill AJ1,9Howell VM1,2Samra J1,3,10Mittal A1,3,10.

Abstract

Background: Neoadjuvant chemotherapy (NAC) has been of recent interest as an alternative to upfront surgery followed by adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). However, a subset of patients does not respond to NAC and may have been better managed by upfront surgery. Hence, there is an unmet need for accurate biomarkers for predicting NAC response in PDAC. We aimed to identify upregulated proteins in tumor tissue from poor- and good-NAC responders. Methods: Tumor and adjacent pancreas tissue samples were obtained following surgical resection from NAC-treated PDAC patients. SWATH-MS proteomic analysis was performed to identify and quantify proteins in tissue samples. Statistical analysis was performed to identify biomarkers for NAC response. Pathway analysis was performed to characterize affected canonical pathways in good- and poor-NAC responders. Results: A total of 3,156 proteins were identified, with 19 being were significantly upregulated in poor-responders compared to good-responders (log2 ratio > 2, p < 0.05). Those with the greatest ability to predict poor-NAC response were GRP78, CADM1, PGES2, and RUXF. Notably, canonical pathways that were significantly upregulated in good-responders included acute phase signaling and macrophage activation, indicating a heightened immune response in these patients. Conclusion: A novel biomarker signature for poor-NAC response in PDAC was identified.

KEYWORDS:

SWATH-MS; biomarkers; neoadjuvant chemotherapy; pancreatic ductal adenocarcinoma; proteomics
14.
 2020 Feb 28;10:234. doi: 10.3389/fonc.2020.00234. eCollection 2020.

Is Hydrogen Sulfide a Concern During Treatment of Lung Adenocarcinoma With Ammonium Tetrathiomolybdate?

Li X1,2Li N1,2Huang L3Xu S4Zheng X1,2Hamsath A4Zhang M1,2Dai L1,2Zhang H1,2Wong JJ5Xian M4Yang CT1,2Liu J1,2.

Abstract

Ammonium tetrathiomolybdate (ATTM) has been used in breast cancer therapy for copper chelation, as elevated copper promotes tumor growth. ATTM is also an identified H2S donor and endogenous H2S facilitates VitB12-induced S-adenosylmethionine (SAM) generation, which have been confirmed in m6A methylation and lung cancer development. The m6A modification was recently shown to participate in lung adenocarcinoma (LUAD) progression. These conflicting analyses of ATTM's anticancer vs. H2S's carcinogenesis suggest that H2S should not be ignored during LUAD's treatment with ATTM. This study was aimed to explore ATTM's effects on LUAD cells and mechanisms associated with H2S and m6A. It was found that treatment with ATTM inhibited cell growth at high concentrations, while enhanced cell growth at low concentrations in three LUAD cell lines (A549, HCC827, and PC9). However, another copper chelator triethylenetetramine, without H2S releasing activity, was not found to induce cell growth. Low ATTM concentrations also elevated m6A content in A549 cells. Analysis of differentially expressed genes in TCGA cohort indicated that m6A writer METTL3 and reader YTHDF1 were upregulated while eraser FTO was downregulated in LUAD tissues, consistent with the findings of protein expression in patient tissues. ATTM treatment of A549 cells significantly increased METTL3/14 and YTHDF1 while decreased FTO expression. Furthermore, inhibition of m6A with shMETTL3 RNA significantly attenuated eukaryotic translation initiation factor (eIF) expressions in A549 cells. Correlation analysis indicated that small nuclear ribonucleic protein PRPF6 was positively expressed with YTHDF1 in LUAD tissues. Knockdown of YTHDF1 partially blocked both basal and ATTM-induced PRPF6 expression, as well as A549 cell growth. Lastly, ATTM treatment not only raised intracellular H2S content but also upregulated H2S-producing enzymes. Exogenous H2S application mimicked ATTM's aforementioned effects, but the effects could be weakened by zinc-induced H2S scavenging. Collectively, H2S impedes ATTM-induced anticancer effects through YTHDF1-dependent PRPF6 m6A methylation in lung adenocarcinoma cells.

KEYWORDS:

Ammonium tetrathiomolybdate; H2S; PRPF6; lung cancer; m6A methylation
15.
 2020 Mar 5;10:233. doi: 10.3389/fonc.2020.00233. eCollection 2020.

The Dual Role of miR-186 in Cancers: Oncomir Battling With Tumor Suppressor miRNA.

Xiang Y1,2Tian Q1Guan L1Niu SS1,3.

Abstract

MicroRNAs (miRNAs) are a class of small non-coding RNAs which regulate gene expression at post-transcriptional level. Alterations of miR-186 expression were demonstrated in numerous cancers, shown to play a vital role in oncogenesis, invasion, metastasis, apoptosis, and drug resistance. MiR-186 was documented as a tumor suppressor miRNA in the majority of studies, while conflicting reports verified miR-186 as an oncomir. The contradictory role in cancers may impede the application of miR-186, as well as other dual-functional miRNAs, as a diagnostic and therapeutic target. This review emphasizes the alterations and functions of miR-186 in cancers and discusses the mechanisms behind the contradictory findings. Among these, target abundance and dose-dependent effects of miR-186 are highlighted. The paper aims to review the challenges involved in developing diagnostic and therapeutic strategies for cancer treatment based on dual-functional miRNAs.

KEYWORDS:

cancer; dual role; miRNA; oncomir; tumor suppressor miRNA
16.
 2020 Mar 3;10:227. doi: 10.3389/fonc.2020.00227. eCollection 2020.

Localization of GPSM2 in the Nucleus of Invasive Breast Cancer Cells Indicates a Poor Prognosis.

Deng M1,2,3Zhang Z4Liu B5,6Hou K5Che X5Qu X5Liu Y5Hu X1Zhang Y7Lv Q4.

Abstract

Purpose: GPSM2 (G protein signaling modulator 2) was reported to be involved in the cell division of breast cancer cells. Additionally, cytoplasmic dynein may mediate the transport process of GPSM2. DYNC1I1 (Cytoplasmic dynein 1 intermediate chain 1) is the most common cargo-binding subunit of dynein. However, the relationship between GPSM2 and DYNC1I1 and its clinical value is unclear. Methods: Immunohistochemical staining was performed for assessment of GPSM2 and DYNC1I1 expression. Immunoprecipitation analysis was used to assess the interaction between GPSM2 and DYNC1I1. Results: GPSM2 was correlated with clinical characteristics of breast cancer patients and is an unfavorable independent prognostic factor. In addition, nuclear expression of GPSM2 is an unfavorable independent prognostic factor (HR = 2.658, 95% CI = 1.490-4.741, p = 0.001). GPSM2 and DYNC1I1 are known to form a complex in breast cancer cells. Patients who were positive for expression of both DYNC1I1 and GPSM2 presented with shorter recurrence-free survival than other patients. Importantly, patients with GPSM2 nuclear expression showed higher DYNC1I1 expression. Conclusion: GPSM2 was an independent prognostic factor in breast cancer and nuclear expression of GPSM2 was significantly associated with poor prognosis, which was related to the positive expression of DYNC1I1. Examination of both GPSM2 and DYNC1I1 is necessary to establish a prognosis in breast cancer patients.

KEYWORDS:

DYNC1I1; GPSM2; breast cancer; prognosis; subcellular localization
17.
 2020 Mar 5;10:224. doi: 10.3389/fonc.2020.00224. eCollection 2020.

Tyrosine Kinase Inhibitors Could Be Effective Against Non-small Cell Lung Cancer Brain Metastases Harboring Uncommon EGFR Mutations.

Ma C1Zhang J2,3Tang D2,3Ye X2,3Li J1Mu N1Li Z4Liu R4Xiang L2,3Huang C2,3Jiang R1.

Abstract

Background: The significance of uncommon epidermal growth factor receptor (EGFR) mutations in patients with non-small cell lung cancer (NSCLC) and brain metastasis (BM) remains unclear. Cerebrospinal fluid (CSF) liquid biopsy is a novel tool for assessing EGFR mutations in BM. This study aimed to evaluate the EGFR mutations in patients with NSCLC and newly diagnosed BM and to examine the effect of EGFR tyrosine kinase inhibitors (TKI) on BM harboring CSF-tested uncommon EGFR mutations. Methods: This was a prospective study of 21 patients with NSCLC and BM diagnosed between 04/2018 and 01/2019. CSF was obtained to detect the BM EGFR mutations by next-generation sequencing. BM characteristics at magnetic resonance imaging (MRI) and EGFR-TKI response were examined. Results: Of 21 patients with NSCLC, 10 (47.6%) had leptomeningeal metastasis (LM), while 11 (52.4%) had brain parenchymal metastasis (BPM); 13 (61.9%) had confirmed EGFR mutation-positive primary tumors. The uncommon mutation rate in CSF ctDNA was 33.3% (7/21). Among those with EGFR mutation-positive primary tumors, the rate of uncommon EGFR mutations in CSF was 53.8% (7/13). Uncommon EGFR mutations were more common in patients with LM than in patients with PBM (6/11, 54.5% vs. 1/10, 10%), and included G719A, L861Q, L703P, and G575R. TKI was effective for four patients with BMs harboring uncommon EGFR mutations. Conclusion: In patients with NSCLC and LM, the rate of uncommon EGFR mutation was high. The BMs with uncommon EGFR mutations seem to respond to EGFR-TKI treatment. CSF liquid biopsy could reveal the EGFR genetic profile of the BM and help guide treatment using small-molecule TKI.

KEYWORDS:

brain metastasis; epidermal growth factor receptor; mutation; non-small cell lung cancer; tyrosine kinase inhibitors
18.
 2020 Mar 5;10:223. doi: 10.3389/fonc.2020.00223. eCollection 2020.

Oncogenic Network and Hub Genes for Natural Killer/T-Cell Lymphoma Utilizing WGCNA.

Liu H1,2Liu M3You H2Li X4Li X1,2,5.

Abstract

Natural killer (NK)/T-cell lymphoma (NKTCL) is a subtype of non-Hodgkin lymphoma with aggressive progression and poor prognosis. The molecular mechanisms of NKTCL have not been well-studied. Herein, we revealed the lymphoma-associated dysregulated genes and signaling pathways or biological processes in NKTCL. We characterized that the extracellular matrix (ECM) receptor interaction pathway and T-cell receptor signaling pathway were the main dysregulated pathways in NKTCL by Gene Ontology (GO) analysis and pathway enrichment analysis. By using weighted gene co-expression network analysis (WGCNA), the gene co-expression network of NKTCL (SRP049695) was constructed, and hub genes (LMO3, GRB14) were identified. In addition, another Gene Expression Omnibus (GEO) dataset (GSE69406) was used to validate these hub genes. Furthermore, these hub genes were identified and validated by survival analysis (GSE90597). These results provided novel insights into the pathogenesis of NKTCL. Of particular interest, LMO3 and GRB14 might be potential oncoproteins and biomarkers for the diagnosis and treatment of NKTCL.

KEYWORDS:

GRB14; LMO3; co-expression network; natural killer/T-cell lymphoma (NKTCL); weight gene co-expression network analysis (WGCNA)
19.
 2020 Mar 5;10:211. doi: 10.3389/fonc.2020.00211. eCollection 2020.

Phosphofructokinase 1 Platelet Isoform Promotes β-Catenin Transactivation for Tumor Development.

Lee JH1Shao F2Ling J3Lu S3Liu R4Du L5Chung JW1Koh SS1Leem SH1Shao J6Xing D2,7An Z8Lu Z9.

Abstract

Metabolism plays a critical role in direct regulation of a variety of cellular activities via metabolic enzymes and metabolites. Here, we demonstrate that phosphofructokinase 1 platelet isoform (PFKP), which catalyzes a rate-limiting reaction in glycolysis, promotes EGFR activation-induced nuclear translocation and activation of β-catenin, thereby enhancing the expression of its downstream genes CCND1 and MYC in human glioblastoma cells. Importantly, we showed that EGFR-phosphorylated PFKP Y64 has a critical role in AKT activation and AKT-mediated β-catenin S552 phosphorylation and subsequent β-catenin transactivation and promotion of tumor cell glycolysis, migration, invasion, proliferation, and brain tumor growth. These findings highlight a novel mechanism underlying a glycolytic enzyme-mediated β-catenin transactivation and underscore the integrated and reciprocal regulation of metabolism and gene expression, which are two fundamental biological processes in tumor development.

KEYWORDS:

PFKP; c-Myc; cyclin D1; invasion; migration; proliferation; β-catenin
20.
 2020 Mar 3;10:205. doi: 10.3389/fonc.2020.00205. eCollection 2020.

Helicobacter pylori Is Associated With Precancerous and Cancerous Lesions of the Gastric Cardia Mucosa: Results of a Large Population-Based Study in China.

Abstract

Background: Helicobacter pylori (H. pylori) is widely accepted to be the most important cause of gastric non-cardia adenocarcinoma (GNCA), while its role in the development of gastric cardia adenocarcinoma (GCA) is not well-defined. We aimed to investigate current H. pylori infection in relation to the severity of both precancerous and cancerous lesions of the gastric cardia in an Asian population at high risk of GCA. Methods: A population-based cross-sectional study was conducted in Linzhou County, Henan Province, China. Two thousand three (2,003) randomly selected participants with data on current H. pylori infection, assayed by 13C-urea breath test (13C-UBT), and a sequence of histological diagnoses of the gastric cardia mucosa were analyzed. Results: Of 2,003 subjects, 828 (41.33%) were currently infected with H. pylori. The prevalence of current H. pylori infection increased with increasing severity of histological lesions, from 34.12% in subjects with normal gastric cardia mucosa to 52.17% in subjects with gastric cardia high-grade intraepithelial neoplasia (CHIN)/ gastric cardia adenocarcinoma (GCA) (P for trend <0.001). With H. pylori-negative subjects as the reference category, H. pylori-positive subjects had statistically significant elevated adjusted prevalence odds ratios (PORs) for each of the histological lesions. The PORs (95% CI) were 2.15 (1.74-2.64), 3.46 (2.08-5.75), 2.78 (1.90-4.07), and 3.05 (1.30-7.17) for subjects with carditis, cardia intestinal metaplasia (CIM), cardia low-grade intraepithelial neoplasia (CLIN), and CHIN/GCA), respectively. The associations remained when subjects with abnormal stomach non-cardia mucosa were excluded. Conclusions: This large epidemiologic study demonstrates a positive association between current H. pylori infection and the severity of both precancerous and cancerous lesions of the gastric cardia in an Asian population at high risk of GCA. These findings suggest that H. pylori infection may play a role throughout both early- and late-stage development of GCA.

KEYWORDS:

13C-urea breath test; Helicobacter pylori; gastric cardia; gastric cardia adenocarcinoma; population-based studies; precursor lesions
21.
 2020 Feb 28;10:199. doi: 10.3389/fonc.2020.00199. eCollection 2020.

Insights About Circadian Clock and Molecular Pathogenesis in Gliomas.

Abstract

The circadian clock is an endogenous time-keeping system that has been discovered across kingdoms of life. It controls and coordinates metabolism, physiology, and behavior to adapt to variations within the day and the seasonal environmental cycles driven by earth rotation. In mammals, although circadian rhythm is controlled by a set of core clock genes that are present in both in suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral tissues, the generation and control of the circadian rhythm at the cellular, tissue, and organism levels occurs in a hierarchal fashion. The SCN is central pacemaker comprising the principal circadian clock that synchronizes peripheral circadian clocks to their appropriate phase. Different epidemiological studies have shown that disruption of normal circadian rhythm is implicated in increasing the risk of developing cancers. In addition, deregulated expression of clock genes has been demonstrated in various types of cancer. These findings indicate a close association between circadian clock and cancer development and progression. Here, we review different evidences of this association in relation to molecular pathogenesis in gliomas.

KEYWORDS:

cancer hallmarks; chronotherapy; circadian clock; glioma; neuro-glial communication
22.
 2020 Mar 4;10:194. doi: 10.3389/fonc.2020.00194. eCollection 2020.

High Levels of BMP2 Promote Liver Cancer Growth via the Activation of Myeloid-Derived Suppressor Cells.

Abstract

Bone morphogenetic protein 2 (BMP2) signaling had significant roles in diverse pathological processes, such as cancer. Nevertheless, the interaction between BMP2 and carcinoma development remained largely unknown. In particular, the roles that BMP2 play in the development of liver cancer remained controversial, and mechanisms were unclear. BMP2 with strong osteogenic potential had been manufactured into various bone materials. However, cancer risk concerns were raised in recent years. Thus, we focused on analyzing the effects of exogenous BMP2 on the growth of liver cancer and the detailed mechanisms. We found that both intravenous injection of rhBMP2 and in vivo implantation of rhBMP2 materials could lead to the expansion of myeloid-derived suppressor cells (MDSCs) in peripheral blood and subsequently enhanced the infiltration of MDSCs into tumor in vivo. Furthermore, BMP2 signaling-activated MDSCs could secrete IL6 to enhance cell proliferation of liver cancer cells in vitro and facilitate liver cancer growth in vivo. Our study indicated that increased concentration of BMP2 within the peripheral blood could enhance liver cancer growth via the activation of MDSCs. In this study, the roles that BMP2 played in liver cancer growth were further confirmed and the detailed mechanisms about how BMP2 enhanced liver cancer growth were also elucidated.

KEYWORDS:

BMP2; IL6; MDSCs; cell proliferation; liver cancer
23.
 2020 Mar 5;10:180. doi: 10.3389/fonc.2020.00180. eCollection 2020.

FAM83A Promotes Lung Cancer Progression by Regulating the Wnt and Hippo Signaling Pathways and Indicates Poor Prognosis.

Zheng YW1Li ZH1Lei L1Liu CC1Wang Z1,2Fei LR1Yang MQ1,3Huang WJ1Xu HT1.

Abstract

FAM83A (family with sequence similarity 83, member A) has been found to be highly expressed in cancers. The purpose of this study was to clarify the role and mechanism of FAM83A in lung cancers. The expression of FAM83A in lung cancer cells was enhanced by gene transfection or knocked down by small interfering RNA interference. The key proteins of the Wnt signaling pathway, the Hippo signaling pathway, and epithelial-mesenchymal transition (EMT) were examined using Western blot. The proliferation and invasion of lung cancer cells were examined using cell proliferation, colony formation, and invasion assays. The expression of FAM83A in lung cancer tissues was significantly increased and was correlated with advanced tumor-node-metastasis (TNM) stage and poor prognosis. Overexpression of FAM83A enhanced the proliferation, colony formation, and invasion of lung cancer cells. Meanwhile, FAM83A overexpression increased the expression of active β-catenin and Wnt target genes and the activity of EMT. Furthermore, in FAM83A-overexpressed cells, the activity of Hippo pathway was downregulated, whereas the expression of yes-associated protein (YAP) and its downstream targets cyclin E and CTGF were upregulated. The inhibitor of the Wnt signaling pathway, XAV-939, reversed the promoting effect of FAM83A on YAP, cyclin E, and CTGF. On knocking down the expression of FAM83A, we obtained the opposite results. However, the inhibitor of GSK3β, CHIR-99021, restored the expression of YAP, cyclin E, and CTGF after FAM83A was knocked down. FAM83A is highly expressed in lung cancers and correlated with advanced TNM stage and poor prognosis. FAM83A promotes the proliferation and invasion of lung cancer cells by regulating the Wnt and Hippo signaling pathways and EMT process.

KEYWORDS:

FAM83A; Hippo signaling pathway; Wnt signaling pathway; epithelial–mesenchymal transition; invasion; lung cancer; proliferation
24.
 2020 Mar 5;10:177. doi: 10.3389/fonc.2020.00177. eCollection 2020.

Interdisciplinary Treatment of Breast Cancer After Mastectomy With Autologous Breast Reconstruction Using Abdominal Free Flaps in a University Teaching Hospital-A Standardized and Safe Procedure.

Abstract

Background: Breast cancer is the most common malignancy in women. The interdisciplinary treatment is based on the histological tumor type, the TNM classification, and the patient's wishes. Following tumor resection and (neo-) adjuvant therapy strategies, breast reconstruction represents the final step in the individual interdisciplinary treatment plan. Although manifold flaps have been described, abdominal free flaps, such as the deep inferior epigastric artery perforator (DIEP) or the muscle-sparing transverse rectus abdominis myocutaneous (ms-TRAM) flap, are the current gold standard for autologous breast reconstruction. This retrospective study focuses on the safety of autologous breast reconstruction upon mastectomy using abdominal free flaps. Methods: From April 2012 until December 2018, 193 women received 217 abdominal free flaps for autologous breast reconstruction at the University Hospital of Erlangen. For perforator mapping, we performed computed tomography angiography (CTA). Venous anastomosis was standardized using a ring pin coupler system, and flap perfusion was assessed with fluorescence angiography. A retrospective analysis was performed based on medical records, the surgery report, and follow-up of outpatient course. Results: In most cases, autologous breast reconstruction was performed as a secondary reconstructive procedure after mastectomy and radiotherapy. In total, 132 ms1-TRAM, 23 ms2-TRAM, and 62 DIEP flaps were performed with 21 major complications (10%) during hospital stay including five free flap losses (2.3%). In all cases of free flap loss, we found an arterial thrombosis as the main cause. In 24 patients a bilateral breast reconstruction was performed without free flap loss. The majority of free flaps (96.7%) did not need additional supercharging or turbocharging to improve venous outflow. Median venous coupler size was 2.5 mm (range, 1.5-3.5 mm). Conclusion: Using CTA, intraoperative fluorescence angiography, titanized hernia meshes for rectus sheath reconstruction, and venous coupler systems, autologous breast reconstruction with DIEP or ms-TRAM free flaps is a safe and standardized procedure in high-volume microsurgery centers.

KEYWORDS:

CTA; DIEP; breast reconstruction; interdisciplinary; ms-TRAM; venous coupler
25.
 2020 Mar 3;10:176. doi: 10.3389/fonc.2020.00176. eCollection 2020.

Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis.

Li WC1,2,3Huang CH1Hsieh YT1Chen TY1Cheng LH1Chen CY1Liu CJ1,2,4,5Chen HM6Huang CL7Lo JF1,2,3,8Chang KW1,2,3,8.

Abstract

To support great demand of cell growth, cancer cells preferentially obtain energy and biomacromolecules by glycolysis over mitochondrial oxidative phosphorylation (OxPhos). Among all glycolytic enzymes, hexokinase (HK), a rate-limiting enzyme at the first step of glycolysis to catalyze cellular glucose into glucose-6-phosphate, is herein emphasized. Four HK isoforms, HK1-HK4, were discovered in nature. It was shown that HK2 expression is enriched in many tumor cells and correlated with poorer survival rates in most neoplastic cells. HK2-mediated regulations for cell malignancy and mechanistic cues in regulating head and neck tumorigenesis, however, are not fully elucidated. Cellular malignancy index, such as cell growth, cellular motility, and treatment sensitivity, and molecular alterations were determined in HK2-deficient head and neck squamous cell carcinoma (HNSCC) cells. By using various cancer databases, HK2, but not HK1, positively correlates with HNSCC progression in a stage-dependent manner. A high HK2 expression was detected in head and neck cancerous tissues compared with their normal counterparts, both in mouse and human subjects. Loss of HK2 in HNSCC cells resulted in reduced cell (in vitro) and tumor (in vivo) growth, as well as decreased epithelial-mesenchymal transition-mediated cell movement; in contrast, HK2-deficient HNSCC cells exhibited greater sensitivity to chemotherapeutic drugs cisplatin and 5-fluorouracil but are more resistant to photodynamic therapy, indicating that HK2 expression could selectively define treatment sensitivity in HNSCC cells. At the molecular level, it was found that HK2 alteration drove metabolic reprogramming toward OxPhos and modulated oncogenic Akt and mutant TP53-mediated signals in HNSCC cells. In summary, the present study showed that HK2 suppression could lessen HNSCC oncogenicity and modulate therapeutic sensitivity, thereby being an ideal therapeutic target for HNSCCs.

KEYWORDS:

cellular malignancy; head and neck cancer; hexokinase 2; metabolic shift; therapeutic efficacy
26.
 2020 Mar 2;10:159. doi: 10.3389/fonc.2020.00159. eCollection 2020.

Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis.

Abstract

Pyruvate kinase plays a pivotal role in regulating cell metabolism. The final and rate-limiting step of glycolysis is the conversion of Phosphoenolpyruvate (PEP) to Pyruvate, which is catalyzed by Pyruvate Kinase. There are four isomeric, tissue-specific forms of Pyruvate Kinase found in mammals: PKL, PKR, PKM1, and PKM2. PKM1 and PKM2 are formed bya single mRNA transcript of the PKM gene by alternative splicing. The oligomers of PKM2 exist in high activity tetramer and low activity dimer forms. The dimer PKM2 regulates the rate-limiting step of glycolysis that shifts the glucose metabolism from the normal respiratory chain to lactate production in tumor cells. Besides its role as a metabolic regulator, it also acts as protein kinase, which contributes to tumorigenesis. This review is focused on the metabolic role of pyruvate kinase M2 in normal cells vs. cancerous cells and its regulation at the transcriptional level. The review also highlights the role of PKM2 as a potential diagnostic marker and as a therapeutic target in cancer treatment.

KEYWORDS:

anaerobic glycolysis; angiogenesis; cancer metabolism; chemotherapy; pyruvate kinase M2
27.
 2020 Mar 4;10:145. doi: 10.3389/fonc.2020.00145. eCollection 2020.

Role of Genetic Ancestry in 1,002 Brazilian Colorectal Cancer Patients From Barretos Cancer Hospital.

Abstract

Background: Colorectal cancer (CRC) is the third most frequent and the second deadliest cancer worldwide. The ethnic structure of the population has been gaining prominence as a cancer player. The purpose of this study was to determine the genetic ancestry of Brazilian CRC patients. Moreover, we intended to interrogate its impact on patients' clinicopathological features. Methods: Retrospective observational cohort study with 1,002 patients with CRC admitted from 2000 to 2014 at Barretos Cancer Hospital. Following tumor DNA isolation, genetic ancestry was assessed using a specific panel of 46 ancestry informative markers. Survival rates were obtained by the Kaplan-Meier method, and the log-rank test was used to compare the survival curves. Multivariable Cox proportional regression models were used to estimate hazard ratios (HRs). Results: We observed considerable admixture in the genetic composition, with the following average proportions: European 74.2%, African 12.7%, Asian 6.5%, and Amerindian 6.6%. The multivariate analysis for cancer-specific survival showed that clinical stage, lymphovascular invasion, and the presence of recurrence were associated with an increased relative risk of death from cancer (p < 0.05). High African proportion was associated with younger age at diagnosis, while high Amerindian proportion was associated with the mucinous histological subtype. Conclusions: This represents the larger assessment of genetic ancestry in a population of Brazilian patients with CRC. Brazilian CRC patients exhibited similar clinicopathological features as described in Western countries. Impact: Genetic ancestry components corroborated the significant admixture, and importantly, patients with high African proportion develop cancer at a younger age.

KEYWORDS:

cancer outcome; colorectal cancer; colorectal cancer survival; genetic ancestry; prognostic factors
28.
 2020 Mar 3;10:138. doi: 10.3389/fonc.2020.00138. eCollection 2020.

The Value of 99mTc-Methylene Diphosphonate Single-Photon Emission Computed Tomography/Computed Tomography in Detecting Atraumatic Costal Cartilage Fracture in Malignant Tumor Patients.

Li W1Zhang L1Li W1Zhang R1.

Abstract

Objectives: To assess the clinical significance and single-photon emission computed tomography/computed tomography (SPECT/CT) features of atraumatic costal cartilage fracture (CCF) in patients with malignant tumors. Methods: This was a retrospective review of 38 tumor patients with atraumatic CCF referred to SPECT/CT, who were served as the study group (SG). The features of SPECT/CT of atraumatic CCF were assessed. Another 100 tumor patients who underwent chest SPECT/CT and did not have CCF were randomly selected as the control group (CG). In all patients (SG + CG), the diagnostic powers in the detection of atraumatic CCF were computed among CT, SPECT, and SPECT/CT. The final diagnosis was based on pathological findings and radiologic follow-up of at least 1 year. Results: On SPECT/CT images of atraumatic CCF in the SG, fracture lines, irregular calcification, deformation, and swelling were, respectively, noted in 26.3, 47.4, 34.2, and 18.4% of lesions; low, moderate, and high uptake were, respectively, noted in 13.2, 52.6, and 34.2% of lesions. In all patients (SG + CG), the diagnostic powers in the detection of atraumatic CCF of CT, SPECT, and SPECT/CT were as follows: sensitivity 63.2, 100.0, and 92.1%; specificity 86.0, 81.0, and 94.0%; negative predictive value 86.0, 100.0, and 96.9%; positive predictive value 63.1, 66.7, and 85.4%; and area under the curve value 0.746, 0.905, and 0.931. Conclusions: Atraumatic CCF has certain characteristic appearances on SPECT/CT. It should be enrolled in the differential diagnoses when costal cartilages of patients with malignant tumors show abnormal elevated 99mTc-MDP uptake on scintigraphy. Single-photon emission computed tomography/CT has excellent diagnostic power in detecting atraumatic CCF.

KEYWORDS:

99mTc-methylene diphosphonate; costal cartilage; fracture; malignant tumor; single-photon emission computed tomography/computed tomography
29.
 2020 Mar 3;10:76. doi: 10.3389/fonc.2020.00076. eCollection 2020.

Carcinoma and Sarcoma Microenvironment at a Glance: Where We Are.

Abstract

Cells and extracellular matrix (ECM) components represent the multifaceted and dynamic environment that distinguishes each organ. Cancer is characterized by the dysregulation of the composition and structure of the tissues, giving rise to the tumor milieu. In this review, we focus on the microenvironmental analysis of colorectal cancer (CRC) and rhabdomyosarcoma (RMS), two different solid tumors. While a lot is known about CRC environment, for RMS, this aspect is mostly unexplored. Following the example of the more complete CRC microenvironmental characterization, we collected and organized data on RMS for a better awareness of how tissue remodeling affects disease progression.

KEYWORDS:

colon rectal cancer; extracellular matrix; microenvironment remodeling; rhabdomyosarcoma; tumor microenvironment

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