The complex cross-talk of intricate intercellular signaling networks between the tumor and stromal cells promotes cancer progression. Hypoxia is one of the most common conditions encountered within the tumor microenvironment that drives tumorigenesis. Most responses to hypoxia are elicited by a family of transcription factors called hypoxia-inducible factors (HIFs), which induce expression of a diverse set of genes that assist cells to adapt to hypoxic environments. Among the three HIF protein family members, the role of HIF-1 is well established in cancer progression. HIF-1 functions as a signaling hub to coordinate the activities of many transcription factors and signaling molecules that impact tumorigenesis. This mini review discusses the complex role of HIF-1 and its context-dependent partners under various cancer-promoting events including inflammation and generation of cancer stem cells, which are implicated in tumor metastasis and relapse. In addition, the review highlights the importance of therapeutic targeting of HIF-1 for cancer prevention.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.29519

HIF-1 at the crossroads of hypoxia, inflammation, and cancer.

During cancer progression, some cells within the primary tumor may reactivate a latent embryonic program known as epithelial-to-mesenchymal transition (EMT). Through EMT, transformed epithelial cells can acquire the mesenchymal traits that seem to facilitate metastasis. Indeed, there is accumulating evidence that EMT and mesenchymal-related gene expression are associated with aggressive breast cancer subtypes and poor clinical outcome in breast cancer patients. More recently, the EMT program was shown to endow normal and transformed mammary epithelial cells with stem cell properties, including the ability to self-renew and efficiently initiate tumors. This link between EMT and stem cells may have numerous implications in the progression of breast tumors. The EMT process may facilitate the generation of cancer cells with the mesenchymal traits needed for dissemination as well as the self-renewal properties needed for initiation of secondary tumors. Breast cancer stem cells are resistant to many conventional cancer therapies, which can promote tumor relapse. Therefore, the generation of cancer stem cells by EMT may promote the development of refractory and resistant breast tumors. The purpose of this review is to summarize the findings related to EMT and stem cells in cancer progression and therapy resistance.

The epithelial-to-mesenchymal transition and cancer stem cells : a coalition against cancer therapies

Activation of the sonic hedgehog (Shh) signaling pathway controls tumorigenesis in a variety of cancers. Here, we show a role for Shh signaling in the promotion of epithelial-to-mesenchymal transition (EMT), tumorigenicity, and stemness in the bladder cancer. EMT induction was assessed by the decreased expression of E-cadherin and ZO-1 and increased expression of N-cadherin. The induced EMT was associated with increased cell motility, invasiveness, and clonogenicity. These progression relevant behaviors were attenuated by treatment with Hh inhibitors cyclopamine and GDC-0449, and after knockdown by Shh-siRNA, and led to reversal of the EMT phenotype. The results with HTB-9 were confirmed using a second bladder cancer cell line, BFTC905 (DM). In a xenograft mouse model TGF-β1 treated HTB-9 cells exhibited enhanced tumor growth. Although normal bladder epithelial cells could also undergo EMT and upregulate Shh with TGF-β1 they did not exhibit tumorigenicity. The TGF-β1 treated HTB-9 xenografts showed strong evidence for a switch to a more stem cell like phenotype, with functional activation of CD133, Sox2, Nanog, and Oct4. The bladder cancer specific stem cell markers CK5 and CK14 were upregulated in the TGF-β1 treated xenograft tumor samples, while CD44 remained unchanged in both treated and untreated tumors. Immunohistochemical analysis of 22 primary human bladder tumors indicated that Shh expression was positively correlated with tumor grade and stage. Elevated expression of Ki-67, Shh, Gli2, and N-cadherin were observed in the high grade and stage human bladder tumor samples, and conversely, the downregulation of these genes were observed in the low grade and stage tumor samples. Collectively, this study indicates that TGF-β1-induced Shh may regulate EMT and tumorigenicity in bladder cancer. Our studies reveal that the TGF-β1 induction of EMT and Shh is cell type context dependent. Thus, targeting the Shh pathway could be clinically beneficial in the ability to reverse the EMT phenotype of tumor cells and potentially inhibit bladder cancer progression and metastasis.

Sonic hedgehog (Shh) signaling promotes tumorigenicity and stemness via activation of epithelial‐to‐mesenchymal transition (EMT) in bladder cancer

Lung cancer and pleural mesothelioma are two of the most deadly forms of cancer. The prognosis of lung cancer and mesothelioma is extremely poor due to limited treatment modalities and lack of understanding of the disease mechanisms. We have identified mesothelin as a potentially unique therapeutic target that as a specific advantage appears nonessential in most cell types. Mesothelin (MSLN), a plasma membrane differentiation antigen, is expressed at a high level in many human solid tumors, including 70% of lung cancer and nearly all mesotheliomas. However, the role of MSLN in the disease process and underlying mechanisms is largely unknown. ShRNA knockdown and overexpression of MSLN were performed in human cancer cell lines and corresponding normal cells, respectively. Tumorigenic and metastatic effects of MSLN were examined by tumor sphere formation, migration, and invasion assays in vitro, as well as xenograft tumor assay in vivo. EMT and CSCs were detected by qPCR array, immunoblotting and flow cytometry. MSLN plays a key role in controlling epithelial-to-mesenchymal transition (EMT) and stem properties of human lung cancer and mesothelioma cells that control their tumorigenicity and metastatic potential. Firstly, MSLN was found to be highly upregulated in non-small cell lung cancer (NSCLC) patient tissues and in lung carcinoma and mesothelioma cell lines. Secondly, genetic knockdown of MSLN significantly reduced anchorage-independent cell growth, tumor sphere formation, cell adhesion, migration and invasion in vitro, as well as tumor formation and metastasis in vivo. Thirdly, ectopic overexpression of MSLN induced the malignant phenotype of non-cancerous cells, supporting its role as an oncogene. Finally, mechanistic studies revealed that knockdown of MSLN reversed EMT and attenuated stem cell properties, in addition to inhibiting tumor growth and metastasis. These results indicate an essential role of MSLN in controlling EMT and stem cell properties of human lung cancer and mesothelioma cells. Since EMT is an important process in tumor progression and metastasis, and MSLN is nonessential in most normal tissue, our findings on MSLN may provide new insights into the disease mechanisms and may aid in the development of novel targeted therapy for lung cancer and mesothelioma.

/pdf/mesothelin-promotes-epithelial-to-mesenchymal-transition-and-ek6p740gss.pdf

Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells

Nearly 30,000 men die annually in the USA of prostate cancer, nearly uniformly from metastatic dissemination. Despite recent advances in hormonal, immunologic, bone-targeted, and cytotoxic chemotherapies, treatment resistance and further dissemination are inevitable in men with metastatic disease. Emerging data suggests that the phenomenon of epithelial plasticity, encompassing both reversible mesenchymal transitions and acquisition of stemness traits, may underlie this lethal biology of dissemination and treatment resistance. Understanding the molecular underpinnings of this cellular plasticity from preclinical models of prostate cancer and from biomarker studies of human metastatic prostate cancer has provided clues to novel therapeutic approaches that may delay or prevent metastatic disease and lethality over time. This review will discuss the preclinical and clinical evidence for epithelial plasticity in this rapidly changing field and relate this to clinical phenotype and resistance in prostate cancer while suggesting novel therapeutic approaches.

The role of epithelial plasticity in prostate cancer dissemination and treatment resistance

Purpose Currently, endoscopic transsphenoidal surgery (ETS) and microscopic transsphenoidal surgery (MTS) are commonly applied treatments for patients with pituitary adenomas. This meta-analysis was conducted to evaluate the efficacy and safety of ETS and MTS for these patients. Methods A computer search of Pubmed, Embase, Cochrane library, Web of Science, and Google Scholar databases was conducted for studies investigating ETS and MTS for patients with pituitary adenomas. The deadline is March 01, 2021. RevMan5.1 software was used to complete this meta-analysis after literature screening, data extraction, and literature quality evaluation. Results A total of 37 studies including 5,591 patients were included. There was no significant difference in gross tumor removal (GTR) and hormone-excess secretion remission (HES remission) between two groups [RR = 1.10, 95% CI (0.99–1.22), P = 0.07; RR = 1.09, 95% CI (1.00–1.20), P = 0.05]. ETS was associated with lower incidence of diabetes insipidus (DI) [RR = 0.71, 95% CI (0.58–0.87), P = 0.0008], hypothyroidism [RR = 0.64, 95% CI (0.47–0.89), P = 0.007], and septal perforation [RR = 0.32, 95% CI (0.13–0.79), P = 0.01] than those with MTS. Conclusion This meta-analysis indicated that ETS cannot significantly improve GTR and HES remission. However, ETS could reduce the incidence of DI, hypothyroidism, and septal perforation without increasing the rate of other complications. Systematic Review Registration https://www.crd.york.ac.uk/prospero/#myprospero, identifier: CRD42021241217.

/pdf/endoscopic-vs-microscopic-transsphenoidal-surgery-for-the-1ide5nc5.pdf

Endoscopic vs. Microscopic Transsphenoidal Surgery for the Treatment of Pituitary Adenoma: A Meta-Analysis

Background Although insulin pump therapy is an important treatment modality for patients with type 1 diabetes, rates of pump use appear to vary broadly internationally. This study aimed to investigate the application of insulin pump therapy among patients with type 1 diabetes in China. Methods Data were collected from the Type 1 Diabetes Mellitus in China: Coverage, Costs and Care Study (3C Study). A total of 779 participants from this cross-sectional study were included. Multivariable logistic regression was used for data analysis. Results The median (interquartile range) age at diagnosis of diabetes was 17 (10–28) years and the duration of diabetes was 4 (1–8) years. Among 779 patients, only 89 patients (11.4%) used an insulin pump to control blood glucose. A statistically significant difference was found in HbA1c favoring insulin pump therapy (8.3 ± 1.7% vs. 9.2 ± 2.6%) without obvious differences for severe hypoglycaemia. There were higher proportions of patients with no smoking, frequent daily intake of fruits and vegetables, and adequate self-blood glucose monitoring among patients with insulin pump therapy as compared to those using multiple daily insulin injections. Logistic regression analysis showed that younger age at diagnosis, longer duration of diabetes, higher education level of family members, and higher household income were associated with the use of an insulin pump. Conclusions Data from 3C Study demonstrated that only a minority of patients with type 1 diabetes in China utilize insulin pump therapy. Insulin pump therapy was associated with better blood glucose control and self-management. Patients with younger age at diagnosis and longer duration of diabetes, and patients with better socioeconomic status were more likely to use an insulin pump.

/pdf/real-world-application-of-insulin-pump-therapy-among-1n0aljxl.pdf

Real-World Application of Insulin Pump Therapy Among Patients With Type 1 Diabetes in China: A Cross-Sectional Study

Clinical and imaging features of phosphaturic mesenchymal tumors.

Increasing evidence has shown that cancer stem cells or tumor initiating cells are the 'root cause' of malignant cancers. However, the exact origin of cancer stem cells still remains obscure in thyroid research. EMT has been implicated in the initiation and conversion of early-stage tumors into invasive malignancies and is associated with the stemness of cancer cells. Based on these facts, a new hypothesis was suggested that EMT induces cancer stem cell generation and tumor progression in human thyroid cancer cells in vitro. In the present study, FTC133 cells identified as EMT-negative cells were used for EMT induction by HIF‑1α transfection. Overexpression of HIF-1α induced FTC133 cells to undergo EMT, downregulated the epithelial markers E-cadherin, upregulated the mesenchymal marker vimentin, and associated with highly invasive and metastatic properties. Most importantly, the induction of EMT promoted the stem-like side population cell proportion in the FTC133 cells. These results indicate that EMT induction promotes CSC traits and cell proportions in the thyroid cancer cells, which implies that EMT could induce cancer stem cell generation and tumor progression in thyroid cancers. Further understanding of the role of EMT and cancer stem cells in cancer progression may reveal new targets for the prevention or therapy of thyroid cancers.

/pdf/epithelial-mesenchymal-transition-triggers-cancer-stem-cell-3ot0wjptc3.pdf

Epithelial-mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells.

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Endoscopic vs. Microscopic Transsphenoidal Surgery for the Treatment of Pituitary Adenoma: A Meta-Analysis

Real-World Application of Insulin Pump Therapy Among Patients With Type 1 Diabetes in China: A Cross-Sectional Study

Clinical and imaging features of phosphaturic mesenchymal tumors.

Epithelial-mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells.