Cancer metastasis is responsible for the vast majority of cancer‐related deaths worldwide. In contrast to numerous discoveries that reveal the detailed mechanisms leading to the formation of the primary tumor, the biological underpinnings of the metastatic disease remain poorly understood. Cancer metastasis is a complex process in which cancer cells escape from the primary tumor, settle, and grow at other parts of the body. Epithelial‐mesenchymal transition and anoikis resistance of tumor cells are the main forces to promote metastasis, and multiple components in the tumor microenvironment and their complicated crosstalk with cancer cells are closely involved in distant metastasis. In addition to the three cornerstones of tumor treatment, surgery, chemotherapy, and radiotherapy, novel treatment approaches including targeted therapy and immunotherapy have been established in patients with metastatic cancer. Although the cancer survival rate has been greatly improved over the years, it is still far from satisfactory. In this review, we provided an overview of the metastasis process, summarized the cellular and molecular mechanisms involved in the dissemination and distant metastasis of cancer cells, and reviewed the important advances in interventions for cancer metastasis.
BackgroundThe advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival.MethodsWhole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study.ResultsThe HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1.ConclusionsThe combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.
Objective To elucidate the role and prognostic significance of lymphocyte activation-gene-3 (LAG-3) in soft tissue sarcoma (STS). Methods The expression of LAG-3 in patient and matched normal blood samples was analyzed by flow cytometry. The localization and prognostic values of LAG-3 + cells in 163 STS patients were analyzed by immunohistochemistry. In addition, the expression of tumor-infiltrating CD3 + T, CD4 + T, and CD8 + T cells and their role in the prognosis of STS were evaluated by immunohistochemistry. The effect of LAG-3 blockade was evaluated in an immunocompetent MCA205 fibrosarcoma mouse model. Results Peripheral CD8 + and CD4 + T cells from STS patients expressed higher levels of LAG-3 than those from healthy donors. LAG-3 expression in STS was significantly associated with a poor clinical outcome ( P = 0.038 ) and was correlated with high pathological grade ( P < 0.001), advanced tumor stage ( P = 0.016). Additionally, LAG-3 expression was highly correlated with CD8 + T-cell infiltration ( r = 0.7034, P < 0.001). LAG-3 was expressed in murine tumor-infiltrating lymphocytes, and its blockade decreased tumor growth and enhanced secretion of interferon-gamma by CD8 + and CD4 + T cells. Conclusions LAG-3 blockade may be a promising strategy to improve the effects of targeted therapy in STS.
BackgroundUnplanned excision (UPE) of soft tissue sarcoma (STS) is often chosen in the early phase by general physicians without any radiological evaluation.PurposeThe present study aimed to evaluate the impact of UPE on the clinical outcomes of patients with STS of the trunk and extremity.Materials and MethodsPatients with STS of the trunk and extremity who underwent R0 resection between 1998 and 2016 were included and divided into the UPE and planned excision (PE) groups. Propensity score matching (PSM) was used to control the selection bias. The endpoints were disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS).ResultsIn total, 458 patients (277 males, 181 females; median age: 43 years) were included: 329 (71.8%) in the PE group and 129 (28.2%) in the UPE group. The follow-up time ranged from 7.1 to 313.78 months, with a median of 112.18 months. UPE patients were more likely to have a smaller or superficial lesion and were more frequently administered adjuvant therapy. After PSM, compared with the PE group, the UPE group had a longer LRFS (P=0.015), but there was no difference between the two groups regarding DSS and MFS. Residual disease was observed in 77.5% of the re-resected specimens in the UPE group and was a risk factor for DSS (P = 0.046) and MFS (P = 0.029) but was not associated with local recurrence (LR) (P=0.475) or LRFS (P=0.334). Moreover, we found no difference in DSS, LRFS or MFS according to the interval from UPE to definitive resection.ConclusionSTS treated with UPE had distinct characteristics. Patients who undergo UPE followed by an additional wide R0 resection have similar oncological survival compared to patients who undergo an initial PE, although the high incidence of residual tumor in the UPE group leads to an unfavorable clinical course.
Background New immunotherapeutic approaches are urgently needed for metastatic rhabdomyosarcoma, which is associated with poor survival and unsatisfactory treatment outcomes. Platelet‐derived growth factor receptor α (PDGFRA) plays an essential role in the onset and development of rhabdomyosarcoma and is a new potential therapeutic target for rhabdomyosarcoma. The objective of this study was to generate humanized PDGFRA single‐chain variable fragment‐based chimeric antigen receptor (CAR)‐modified T cells (CAR‐T cells) against PDGFRA‐positive rhabdomyosarcoma. Methods PDGFRA antigen expression was evaluated in specimens from patients with rhabdomyosarcoma. CAR‐T cells containing a PDGFRA‐specific single‐chain variable fragment was developed in combination with a 4‐1BB costimulatory domain and a CD3‐ζ signaling domain. Specific cytotoxic effects of PDGFRA CAR‐T cells, T‐cell proliferation, and cytokine secretion were investigated in vitro and in vivo. Results PDGFRA CAR‐T cells produced large amounts of immune‐promoting cytokines, including interleukin 2, tumor necrosis factor α, and interferon γ, and exhibited efficient cytotoxic activity toward human PDGFRA‐overexpressing rhabdomyosarcoma cells in vitro. In a subcutaneous xenograft model, CAR‐T cells were more effective against PDGFRA‐overexpressing rhabdomyosarcoma than against rhabdomyosarcoma with low PDGFRA expression in terms of tumor regression and patient survival. Expanded CAR‐T cells also were detected in peripheral blood. Conclusions The current study demonstrates for the first time that the PDGFRA antigen is a promising target for CAR‐T–cell therapy in rhabdomyosarcoma and likely in a wide spectrum of other PDGFRA‐expressing cancers.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.