Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers. Nevertheless, the low response rate of α-PD-1/PD-L1 therapy remains to be resolved. For most cancer patients, PD-1/PD-L1 pathway is not the sole speed-limiting factor of antitumor immunity, and it is insufficient to motivate effective antitumor immune response by blocking PD-1/PD-L1 axis. It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher response rates. Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity. These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment. In this review, we summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies. Moreover, we focused on the advances of α-PD-1/PD-L1-based immunomodulatory strategies in clinical studies. Given the heterogeneity across patients and cancer types, individualized combination selection could improve the effects of α-PD-1/PD-L1-based immunomodulatory strategies and relieve treatment resistance.
EGFRvIII was first reported in human glioblastomas. Subsequent reports indicated EGFRvIII protein to be frequently detected in several other human cancers, but not in normal tissues. Our previous studies suggested that EGFRvIII could induce a transformation from ligand-dependent non-tumorigenic cell line to ligand-independent malignant phenotype cells in vitro and in vivo. Transfection of EGFRvIII in MCF-7 cell line resulted in a 3-fold increase in colony formation and significantly enhanced tumorigenicity in nude mice (p < 0.001). EGFRvIII could also induce ErbB-2 phosphorylation. The existence and significance of EGFRvIII transcript in human breast cancer, however, was not reported. In our study, we detected the presence of EGFRvIII mRNA and revealed a high incidence (67. Key words: EGFRvIII; EGFR; LCM; breast cancerDevelopment and progression of breast cancer may result from an accumulation of varied aberrations of genes and their products. Detecting and understanding important molecules will address their roles in carcinogenesis and may be considered to be the prerequisite for the genesis of molecular therapeutics in breast cancer treatment. Overexpression of epidermal growth factor receptor (EGFR) has been detected in a variety of human cancers with 15-90% detection rates, and therefore, it has been thought a possible candidate for cancer therapy. [1][2][3][4][5][6] A relationship between overexpression of EGFR and increased metastatic potential and poor prognosis in breast cancers has been reported. 7,8 EGFRvIII, the most common deletion receptor of EGFRwt, was first reported in human glioblastomas. 9 -11 Subsequently, a few reports demonstrated that EGFRvIII protein was also detected in other human cancers, including breast, ovarian, lung, and medulloblastomas, 12,13 but not in normal tissue. 13,14 In our previous studies, we have observed a high incidence of EGFRvIII protein (62%) in human invasive breast cancer and demonstrated a significantly enhanced tumorigenicity in EGFRvIII transfected MCF-7 breast cancer cells in nude mice. 15,16 Studies to confirm the presence and significance of EGFRvIII transcript and protein in breast cancer, however, are still underdeveloped.To further confirm our early immunohistochemistry results and to ascertain EGFRvIII mRNA expression in human breast cancer tissue to explore the possible role of EGFRvIII in breast cancer genetics, we applied the laser capture microdissection (LCM) combined with RT-PCR detection. The PixCell LCM, a newly developed state-of-the-art technique, allows precise capture of specific cells from tissues comprising mixed cell types. 17,18 LCM can procure pure cell populations for molecular analysis by adhering the selected cells to a thermoplastic film through laser pulse. [17][18][19][20] By applying this technique, we were able to preferentially select "pure" breast cancer cells from mixed cell populations of breast tissues for genetic study. As a result, we detected a high incidence (67.8%) of EGFRvIII transcripts in primary invasive breast can...
Vasculogenic mimicry (VM) describes the process utilized by highly aggressive cancer cells to generate vascular-like structures without the presence of endothelial cells. VM has been vividly described in various tumors and participates in cancer progression dissemination and metastasis. Diverse molecular mechanisms and signaling pathways are involved in VM formation. Furthermore, the patterning characteristics of VM, detected with molecular imaging, are being investigated for use as a tool to aid clinical practice. This review explores the most recent studies investigating the role of VM in tumor induction. Indeed, the recognition of these advances will increasingly affect the development of novel therapeutic target strategies for VM in human cancer.
Colorectal cancer (CRC) is a global healthcare problem. Radioresistance is a huge setback for CRC radiotherapy. In this text, the roles and molecular mechanisms of long non-coding RNA HOTAIR in CRC tumorigenesis and radioresistance were further investigated. ATG12 mRNA, HOTAIR, and microRNA-93 (miR-93) levels were measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay. Protein levels of LC3 I, LC3 II, p62, ATG12, cleaved caspase 3, Bax, and Bcl-2 were detected by western blotting assay in cells and were examined by immunohistochemistry (IHC) assay in tissues. Cell survival fractions, viability, and apoptotic rates were determined by clonogenic survival assay, CCK-8 assay, and flow cytometry analysis, respectively. The relationships of HOTAIR, miR-93, and ATG12 were tested by bioinformatics analysis and luciferase reporter assay. Mouse xenograft tumor models were established to investigate the influence of HOTAIR knockdown on CRC radioresistance in vivo. We found that HOTAIR expression was markedly upregulated in plasma from CRC patients after radiotherapy and CRC cells after irradiation. HOTAIR knockdown, miR-93 overexpression, or ATG12 silencing weakened cell viability, induced cell apoptosis, inhibited cell autophagy, and enhanced cell radiosensitivity in CRC. HOTAIR exerted its functions by downregulating miR-93. Moreover, HOTAIR functioned as a molecular sponge of miR-93 to regulate ATG12 expression. ATG12 protein expression was markedly upregulated and associated with miR-93 and HOTAIR expression in CRC tissues. Furthermore, HOTAIR knockdown enhanced radiosensitivity of CRC xenograft tumors by regulating miR-93/ATG12 axis. In conclusion, HOTAIR knockdown potentiated radiosensitivity through regulating miR-93/ATG12 axis in CRC, further elucidating the roles and molecular basis of HOTAIR in CRC radioresistance.
Dosimetric characteristics of AIP plans are similar to those of FB plans. Slightly better target volume coverage and significantly lower low-dose region (≤30 Gy) in lung was observed in MIP plans. The decrease in low-dose region in lung was mainly caused by the change of lung volume contoured on two datasets rather than the differences of dose distribution between AIP and MIP plans. Compare with AIP datasets, FB datasets were more prone to significant image artifacts and MIP datasets may overestimate or underestimate the target volume when the target is closer to the denser tissue, so AIP seems favorable for planning and dose calculation for lung SBRT.
This study compared treatment outcomes between TKI monotherapy and TKI administration combined with brain radiotherapy (TKI + RT) in 133 non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). We also evaluated the association of different epidermal growth factor receptor (EGFR) mutation subtypes with treatment outcome. To screen for potential variables affecting cranial progression free survival (PFS) and overall survival (OS), we performed univariate and multivariate analysis based on Cox proportional-hazards models. Median cranial PFS and OS were longer for the TKI + RT group (n = 67) than TKI alone group (n = 66). Intracranial metastasis correlated with a better median OS than extracranial metastasis. For patients with exon 21 mutations, TKI + RT yielded a better median OS and cranial PFS than TKI alone. However, there were no significant differences in median OS and cranial PFS between the two treatment groups for patients with exon 19 deletions. Thus EGFR-mutant NSCLC patients with BM could benefit more from TKI + RT than from TKI monotherapy, especially when they suffer from exon 21 mutations. However, TKI + RT confers no advantage over TKI treatment alone for patients with exon 19 deletions. These results underscore the urgent need to develop individualized disease management strategies in clinical practice.
Transducer of ErbB-2 (TOB) is a member of the TOB/Btg gene family. A role for TOB in the suppression of human tumorigenesis has been proposed, based on the observations that TOB-knockout mice spontaneously form tumors and TOB expression is lost in human lung and thyroid cancers. However, the role of TOB in human breast cancer remains unknown. To evaluate the this role, we screened a panel of breast cancer cell lines for TOB expression levels and found that they are inversely correlated with the tumorigenicity and metastatic potential of the cell lines. In addition, we demonstrated for the first time that TOB expression is inversely correlated with breast cancer progression in clinical specimens. These results strongly indicate that the loss of TOB expression plays a role in breast cancer progression. We have also provided the first evidence that TOB functions as a tumor suppressor in breast cancer MCF-7 cells, using gain-of-function and loss-offunction approaches to manipulate TOB expression. Cell-cycle analysis further revealed that TOB can prolong the G1-S phase transition by inducing arrest at G1-S phase. Moreover, upregulation of the cyclin-dependent kinase inhibitor p27 and downregulation of the antiapoptotic proteins Bcl-2 and Bcl-XL were observed in MCF7/TOB transfectants. Conversely, opposite results were observed in shRNA-TOB transfectants. Furthermore, decreased activity of Erk2, AKT, CrkL, PDK1, and Smads were observed in TOB-overexpressing cells. Taken together, these data provide evidence that TOB can function as a tumor suppressor in breast cancer through modulation and regulation of multiple signaling pathways. ' UICCKey words: TOB; ErbB-2; tumor suppressor Cell growth and differentiation in normal tissues are controlled by a balance of 2 opposing signaling pathways, namely positive and negative signaling. A Transducer of ErbB-2 (TOB), known as TOB/TOB1, is ubiquitously expressed in human adult tissues and was first identified by screening an expression library that detected protein-protein interactions with an ErbB2 probe. 1 The TOB gene is located on chromosome 17q21, telomeric to the BRCA1 locus. TOB is a 45-kDa protein belonging to the TOB/BTG family, which includes proteins, such as PC3/TIS21/BTG2, BTG1, TOB2, ANA, BTG3, PC3K and others. These proteins share a highly conserved amino-terminal region known as the Btg homology domain.Overexpression of TOB/BTG family proteins negatively regulates the cell cycle by inhibiting G1 progression. 1,2-7 Conversely, the antiproliferative activity of TOB is impaired in the presence of exogenously coexpressed Cyclin D1. 7 TOB's antiproliferative activity is regulated through phosphorylation and nuclear localization. In its active state, TOB is unphosphorylated and it is inactivated by phosphorylation. Growth factor stimulation of the RTK/Ras/MAPK pathway results in rapid phosphorylation of these sites by Erk1and Erk2. 8 TOB is also phosphorylated via the Akt pathway by the serine/threonine kinase p90rsk1. 9 In addition, the antiproliferative activity of ...
Background: Increasing evidence indicates a relationship between systemic inflammation and survival following treatment in various tumors. However, the correlation of systematic inflammation with survival after stereotactic ablative radiotherapy (SABR) in early stage non-small cell lung cancer (NSCLC) has not been well established.Patients and methods: We retrospectively analyzed patients with newly diagnosed early stage NSCLC treated with SABR in a single institution from 2011 to 2015. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte- monocyte ratio (LMR) were calculated as systemic inflammation biomarkers. Overall survival (OS) was the first end-point. Receiver operating characteristic (ROC) was used to determine cut-off points for OS. Univariate and multivariate Cox proportional hazards regression were used to investigate the potential factors associated with OS.Results: In the 63 patients who were eligible for analysis. The median follow up after SBRT was 29.5 months (range 8-67 months) while the 3-year OS was 74.2%. Based on ROC analysis, optimal cut-off values of NLR, PLR, and LMR were 2.06, 199.55 and 4.0, respectively. Significant survival benefit was found in the NLR ≤2.06 group (p=0.028), PLR≤199.55 group (p=0.001), and LMR˃4.0 group (p=0.046). Univariate analysis indicated that low NLR (p=0.011), low PLR (p=0.003), and high LMR (p=0.014) were correlated with improved survival. Multivariate analysis indicated that high PLR (p=0.033) and low LMR (p=0.046) were independent prognostic factors for poor survival.Conclusions: In patients of early stage NSCLC who received SABR, pretreatment NLR, PLR, and LMR could be considered useful prognostic indicators of OS. These metrics may provide reliable and convenient predictors to identify patients who would benefit from SABR.
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