Tumor growth and metastasis depend on the establishment of tumor vasculature to provide oxygen, nutrients, and other essential factors. The well-known vascular endothelial growth factor (VEGF) signaling is crucial for sprouting angiogenesis as well as recruitment of circulating progenitor endothelial cells to tumor vasculature, which has become therapeutic targets in clinical practice. However, the survival benefits gained from targeting VEGF signaling have been very limited, with the inevitable development of treatment resistance. In this article, we discuss the most recent findings and understanding on how solid tumors evade VEGF-targeted therapy, with a special focus on vessel co-option, vessel remodeling, and tumor cell-derived vasculature establishment. Vessel co-option may occur in tumors independently of sprouting angiogenesis, and sprouting angiogenesis is not always required for tumor growth. The differences between vessel-like structure and tubule-like structure formed by tumor cells are also introduced. The exploration of the underlying mechanisms of these alternative angiogenic approaches would not only widen our knowledge of tumor angiogenesis but also provide novel therapeutic targets for better controlling cancer growth and metastasis.
The tumor microenvironment orchestrates the sustained growth, metastasis and recurrence of cancer. As an indispensable component of the tumor microenvironment, cancer‐associated fibroblasts (CAF) are considered as an essential synthetic machine producing various tumor components, leading to cancer sustained stemness, drug resistance and tumor recurrence. Here, we developed a sustainable primary culture of lung cancer cells fed with lung cancer‐associated fibroblasts, resulting in enrichment and acquisition of drug resistance in cancer cells. Moreover, IGF2/AKT/Sox2/ABCB1 signaling activation in cancer cells was observed in the presence of CAF, which induces upregulation of P‐glycoprotein expression and the drug resistance of non‐small cell lung cancer cells. Our results demonstrated that CAF cells constitute a mechanism for cancer drug resistance. Thus, traditional chemotherapy combined with insulin‐like growth factor 2 (IGF2) signaling inhibitor may present an innovative therapeutic strategy for non‐small cell lung cancer therapy.
Rat pituitary GH cells have been used extensively to study the biochemical actions of TRH on lactotropic cells. To investigate the structure and regulation of the rat TRH receptor (rTRHR), we have cloned its cDNA from GH4C1 cells. Using the polymerase chain reaction with degenerate primers and pools of cloned cDNAs from a GH4C1 cDNA library, a fragment sharing high similarity to the mouse thyrotrope TRHR (mTRHR) was identified. Conventional library screening with this fragment was used to isolate a single cDNA. mRNA synthesized in vitro from this cDNA was injected into Xenopus oocytes, and a characteristic conductance response to TRH was detected by voltage clamp recording. DNA sequence analysis revealed a molecule of 412 amino acid residues, with 96% similarity to the mTRHR. However, in contrast to the mTRHR, the rTRHR had an additional 19 amino acid residues at its carboxy-terminus. A mRNA of about 4 kilobases was identified in GH3 cells. Regulation of the rTRHR mRNA concentration was studied in GH3 cells. Steady state rTRHR mRNA levels were decreased to 30% of the control level by incubation with TRH for 48 h and increased 4-fold by incubation with dexamethasone for 12 h. Southern blot analysis of genomic DNA from GH3 cells gave a simple banding pattern consistent with a single copy gene. We conclude that the rTRHR shares high primary sequence similarity to the mTRHR, but the rTRHR has an extension of 19 amino acids at its carboxy-terminus, which is lacking in the mTRHR.
Although risk has always been at the center of entrepreneurship, research on risk recognition in new ventures is limited. Applying cognitive information-processing theory, we develop a theoretical framework that explores the interactive influences of entrepreneurs' social networks and their cognitive characteristics on the outcomes of risk recognition. We test the framework on a sample of 226 Chinese entrepreneurs. The results show that network size, tie strength and structural holes enhance risk recognition outcomes and that cognition (i.e. risk propensity and illusion of control) generally reduces such effects, except in the case of illusion of control, which has no effect on structural holes.
Background Circular RNAs (circRNAs) is a newly discovered non-coding RNA that can be used as biomarkers in clinical blood samples. This study aims to screen differentially expressed circular RNAs in PBMCs of patients with rheumatoid arthritis (RA) to determine new biomarkers for the diagnosis of RA. Methods The differentially expressed circRNAs in peripheral blood mononuclear cells (PBMCs) of 4 RA patients and 4 healthy participants were screened and analyzed by gene microarray technology. We then validated some of the differentially expressed circRNAs in PBMCs of 20 RA patients, 10 systemic lupus erythematosus (SLE) patients and 20 healthy participants using reverse transcription-quantitative polymerase chain reaction amplification (RT-qPCR). Spearman correlation test was performed to analyze the correlation between differentially expressed circRNAs and clinical variables in RA patients. Receiver operating characteristic (ROC) curves were calculated to evaluate the diagnostic value of circRNAs. Results Differential analysis obtained 149 circRNAs with significant up-regulated expression and 250 circRNAs with significant down-regulated expression, which predicted the miRNA targets and binding sites. Compared with SLE and health control group, hsa_circ_101328 was found to be a common gene with differential expression of RA. Besides, correlation analysis revealed significant correlation between hsa_circ_101328 and positive CRP. ROC curve analysis showed that hsa_circ_101328 has the potential of RA diagnosis. Conclusion We identified some dysregulated circRNAs in PBMCs from RA patients, and hsa_circ_101328 may be a novel and effective biomarker for early diagnosis of RA.
The underlying molecular mechanism driving clear cell renal cell carcinoma (ccRCC) progression is still to be explored. The significant downregulation of protein tyrosine phosphatase non-receptor type 3 (PTPN3) expression in the tumor tissues suggested its protective role in ccRCC progression. Immunohistochemical analysis of PTPN3 protein in 172 ccRCC tissue revealed that PTPN3 was an independently favorable prognostic factor for progression-free survival (P = 0.0166) and overall survival (P = 0.0343) of patients. The ccRCC cell lines SN12C, 1932, ACHN and Caki-1 were used to evaluate, both in vitro and in vivo, the biological roles of PTPN3. We observed that overexpression of PTPN3 significantly inhibited the proliferation, migration, and invasion of ccRCC cells. In contrast, the knocking down of PTPN3 elicited opposite effects. Overexpressing PTPN3 inhibited xenograft tumor growth and lung metastasis in vivo mice models. PTN3 inhibited tumor cell motility by suppressing the phosphorylation of AKT, and subsequently inactivating the PI3K/AKT signaling pathway of renal cell carcinoma cells. Further, the inhibition of phospho-AKT Thr308 and phospho-AKT Ser473 reversed PTPN3 induced-silencing in tumor cell migration. Our work revealed that the overexpression of PTPN3 could suppress kidney cancer progression by negatively regulating the AKT signaling pathway, and served as a favorable prognostic factor in ccRCC patients. Our findings provided insight that PTPN3 could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC. ImplicationsPTPN3 is an independent favorable prognostic factor for ccRCC patients and could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC.
BackgroundAverage postoperative follow-up intervals vary in patients undergoing hepatocellular carcinoma (HCC) resection because of limited evidence regarding the optimal interval. We aimed to compare the associations of long-versus short-interval follow-up with survival and recurrence in risk-stratified HCC patients.MethodsWe performed a retrospective cohort study between 2007 and 2014. In total, 1227 patients treated by curative resection of Barcelona Clinic Liver Cancer stage A or B HCC were stratified as having a low (n = 865) or high (n = 362) risk of early recurrence (within the first 2 years after resection) based on prognostic factors identified by the least absolute shrinkage and selection operation algorithm. Patients were further classified into long-interval (every 4–6 months) and short-interval (every 2–4 months) follow-up subgroups based on follow-up within 2 years after resection (low risk, long vs. short: n = 390 vs. n = 475; high-risk, long vs. short: n = 149 vs. n = 213).ResultsThe short-interval follow-up did not prolong overall survival in either the low-risk (hazard ratio [HR] = 1.152; 95% confidence interval [CI] 0.720–1.843) or high-risk (HR = 1.213; 95% CI 0.702–2.094) patients. Early recurrence occurred in 401 patients. For high-risk patients, the short-interval follow-up subgroup exhibited smaller intrahepatic recurrence than did the long-interval group (2.6 vs. 3.5 cm, respectively, P = 0.045). However, no significant difference in the rate of Barcelona Clinic Liver Cancer stage 0/A recurrence was found between the long- and short-interval follow-up groups in either low- or high-risk patients (63.1% vs. 68.2%, respectively, P = 0.580; 31.3% vs. 41.5%, respectively, P = 0.280). The rate of curative intent treatment for recurrence (34.5% vs. 39.7%, respectively, P = 0.430; 14.6% vs. 20.3%, respectively, P = 0.388) was also similar between the follow-up groups for low- and high-risk patients.ConclusionsShortening the postoperative follow-up interval from every 4–6 months to every 2–4 months within the first 2 years after resection did not increase the rate of curative intent treatment or prolong the overall survival of patients with Barcelona Clinic Liver Cancer stage A or B HCC.
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