Targeting claudins in cancer: diagnosis, prognosis and therapy

xlomafota13 shared this article with you from Inoreader Targeting claudins in cancer: diagnosis, prognosis and therapy Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3406-3424. eCollection 2021. ABSTRACT Increasing evidence has linked claudins to signal transduction and tumorigenesis. The expression of claudins is frequently dysregulated in the context of neoplastic transformation, suggesting their promise as biomarkers for diagnosis and prognosis or targets for treatment. Claudin binders (Clostridium perfringens enterotoxin and monoclonal antibody) have been tested in preclinical experiments, and some of them have progressed into clinical trials involving patients with certain cancers. However, the clinical development of many of these agents has not advanced to clinical applications. Herein, I review the current status of preclinical and clinical investigations of agents targeting claudins for diagnosis, prognosis and therapy. I also discuss the potential of combining claudin binders with other currently approved therapeutic agents. PMID:34354852 | PMC:PMC8332862 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Genomic and transcriptomic alterations in m6A regulatory genes are associated with tumorigenesis and poor prognosis in head and neck squamous cell carcinoma

xlomafota13 shared this article with you from Inoreader Genomic and transcriptomic alterations in m6A regulatory genes are associated with tumorigenesis and poor prognosis in head and neck squamous cell carcinoma Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3688-3697. eCollection 2021. ABSTRACT Genetic alterations in N6-methyladenosine (m6A) regulatory genes are observed in many cancers. Recent studies have shown that newly identified m6A regulatory gene family (IGF2BPs; IGF2BP1, IGF2BP2, and IGF2BP3) were highly expressed in various types of cancer that stabilize and promote translation of multiple oncogenes, resulting in tumor development, survival and drug resistance. However, the oncogenic roles and prognostic values of IGF2BPs in head and neck squamous cell carcinoma (HNSCC) remain largely unknown. In this study, we examined the m6A regulatory genes alteration, their mRNAs expression and the prognostic values in HNSCC. We also analyzed the interaction network and functional enrichment of m6A regulators. Our results showed that m6A regulatory genes were altered in 41% (205/504) of HNSCC patients, of which IGF2BP2 was amplified in 20% (101/504) of HNSCC patents and positively correlated with its mRNA expression. Importantly, we have validated the expression of IGF2BP2 in HNSCC and normal tissue samples. Interestingly, we also found that the IGF2BP2 was frequently co-amplified with the most common oncogenes in HNSCC patients. In addition, this study found that other m6A regulatory genes such as METTL3, METTL14, WTAP, KIAA1429, ZC3H13, RBM15, ALKBH5, FTO, YTHDF1, YTHDF2, YTHDF3, YTHDC1, IGF2BP1, and IGF2BP3 were significantly upregulated in HNSCC samples. Moreover, patients with high expression of IGF2BP1, IGF2BP2, and IGF2BP3 had poor overall survival (OS) than those with low expression. Therefore, it is evident that IGF2BP family plays a key role in the oncogenesis of HNSCC and might serve as novel prognostic biomarkers and potential therapeutic targets in HNSCC. PMID:34354868 | PMC:PMC8332867 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Microenvironment of mammary fat pads affected the characteristics of the tumors derived from the induced cancer stem cells

xlomafota13 shared this article with you from Inoreader Microenvironment of mammary fat pads affected the characteristics of the tumors derived from the induced cancer stem cells Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3475-3495. eCollection 2021. ABSTRACT Breast cancer is the first common cause of cancer-related death in women worldwide. Since the malignancy and aggressiveness of breast cancer have been correlated with the presence of breast cancer stem cells, the establishment of a disease model with cancer stem cells is required for the development of a novel therapeutic strategy. Here, we aimed to evaluate the availability of cancer stem cell models developed from mouse induced pluripotent stem cells with the conditioned medium of different subtypes of breast cancer cell lines, the hormonal-responsive T47D cell line and the triple-negative breast cancer BT549 cell line, to generate in vivo tumor models. When transplanted into the mammary fat pads of BALB/c nude mice, these two model cells formed malignant tumors exhibiting pronounced histopathological characteristics similar to breast cancers. Serial tran splantation of the primary cultured cells into mammary fat pads evoked the same features of breast cancer, while this result was perturbed following subcutaneous transplantation. The tumors formed in the mammary fat pads exhibited immune reactivities to prolactin receptor, progesterone receptor, green florescent protein, Ki67, CD44, estrogen receptor α/β and cytokeratin 8, while all of the tumors and their derived primary cells exhibited immunoreactivity to estrogen receptor α/β and cytokeratin 8. Cancer stem cells can be developed from pluripotent stem cells via the secretory factors of cancer-derived cells with the capacity to inherit tissue specificity. However, cancer stem cells should be plastic enough to be affected by the microenvironment of specific tissues. In summary, we successfully established a breast cancer tumor model using mouse induced pluripotent stem cells developed from normal fibroblasts without genetic manipulation. PMID:34354856 | PMC:PMC8332865 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Targeting mitotic exit in solid tumors

xlomafota13 shared this article with you from Inoreader Targeting mitotic exit in solid tumors Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3698-3710. eCollection 2021. ABSTRACT Targeting mitosis by taxanes is one of the most common chemotherapeutic approaches in various malignant solid tumors, but cancer cells may survive antimitotic treatment with attainable in vivo concentrations due to mitotic slippage with a residual activity of the ubiquitin ligase anaphase-promoting complex (APC/C) and a continuous slow ubiquitin-proteasome-dependent cyclin B-degradation leading to mitotic exit. Therefore, blocking cyclin B-proteolysis via additional proteasome (PI) or APC/C-inhibition may have the potential to enhance tumor cell eradication by inducing a more robust mitotic block and mitotic cell death. Here, we analyzed this approach in different cell lines and more physiological patient-derived xenografts (PDX) from lung and breast cancer. The sequential combination of paclitaxel with the PI bortezomib enhanced cell death, but in contrast to the hypothesis during interphase and not in mitosis in both lung and breast cancer. APC/C-inhibition alone or in sequential combination with paclitaxel led to strong mitotic cell death in lung cancer. But in breast cancer, with high expression of the anti-apoptotic regulator Mcl-1, cell death in interphase was induced. Here, combined APC/C- and Mcl-1-inhibition with or without paclitaxel was highly lethal but still resulted in interphase cell death. Taken together, the combination of antimitotic agents with a clinically approved PI or inhibitors of the APC/C and Mcl-1 is a promising approach to improve treatment response in different solid tumors, even though they act entity-dependent at different cell cycle phases. PMID:3435 4869 | PMC:PMC8332852 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

CR13626: a novel oral brain penetrant tyrosine kinase inhibitor that reduces tumor growth and prolongs survival in a mouse model of glioblastoma

xlomafota13 shared this article with you from Inoreader CR13626: a novel oral brain penetrant tyrosine kinase inhibitor that reduces tumor growth and prolongs survival in a mouse model of glioblastoma Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3558-3574. eCollection 2021. ABSTRACT Glioblastoma multiforme (GBM) is the most malignant primary brain cancer. Despite aggressive treatments currently there is no cure for GBM. Many challenges should be considered for the development of new therapeutical agents for glioblastoma, including appropriate target selectivity and pharmacokinetics. Several mutations and alterations of key cellular pathways including tyrosine kinases (TKs) are involved in malignant transformation and tumor progression. Thus, the targeting of multiple pathways and the development of innovative combination drug regimens is expected to yield improved therapies. Moreover, the abilities to cross the blood-brain barrier (BBB) reaching effective concentrations in brain and to remain into this tissue avoiding the effects of efflux transporters are also critical issues in the development of new therapeutics for GBM. CR13626 is a novel brain penetrant small molecule able to potently inhibit in vitro the activity of EGFR, VEGFR2 (aka KDR), Fyn, Yes, Lck, HGK (aka MAP4K4) and RET kinases relevant for GBM development. CR13626 shows good oral bioavailability (72%) and relevant brain penetration (brain/plasma ratio of 1.4). In an orthotopic xenograft glioblastoma mouse model, oral treatment with CR13626 results in a time-dependent reduction of tumor growth, leading to a significant increase of animal survival. The unique properties of CR13626 warrant its further investigation as a potential new drug candidate in glioblastoma. PMID:34354860 | PMC:PMC8332859 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Predictors of long-term recurrence and survival after resection of HBV-related hepatocellular carcinoma: the role of HBsAg

xlomafota13 shared this article with you from Inoreader Predictors of long-term recurrence and survival after resection of HBV-related hepatocellular carcinoma: the role of HBsAg Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3711-3725. eCollection 2021. ABSTRACT The recurrence rate remains high even under nucleos(t)ide analogues (NUCs) therapy in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after resection. The aim of this study is to evaluate the prognostic role of HBsAg in patients undergoing surgical resection for HBV-related HCC in NUCs era. Consecutive 522 patients undergoing surgical resection for HBV-related HCC were retrospectively enrolled. Factors associated with early (within 2 years), late (year 2 to 5), very late (beyond 5 years) recurrence and early or late mortality (within or beyond 5 years) were evaluated. During a median follow-up period of 59 months, 308 (59%), and 146 (28%) patients developed recurrence and mortality, respectively. HBsAg level did not correlate with early recurrence and mortality. By multivariate analyses, HBsAg >200 IU/mL (hazard ratio (HR)=1.778, P= 0.037) and presence of cirrhosis (HR=2.157, P=0.001) were independent predictors of late recurrence, while HBsAg >50 IU/mL (HR=4.658, P=0.038), body mass index >25 kg/m2 (HR=2.720, P=0.013) and significant hepatic fibrosis (HR=2.509, P=0.039) were independent predictors of very late recurrence. HBsAg >50 IU/mL (HR=11.427, P=0.017), age >60 years (HR=2.688, P=0.006), albumin ≤3.5 g/dL (HR=4.739, P<0.001) and presence of cirrhosis (HR=2.781, P=0.006) were independent predictors of late mortality beyond 5 years. Combining these factors could well predict patients with minimal risk of long-term recurrence and mortality. In conclusion, tumor factors, liver function surrogate markers, metabolic factors and serum HBsAg levels play distinct roles in recurrence and survival at different time intervals after surgical resection for HBV-related HCC. Pre-operative HBsAg level is an important predictor of long-term recurrence and survival in patients with HBV-related H CC undergoing surgical resection. PMID:34354870 | PMC:PMC8332858 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Nab-paclitaxel promotes the cancer-immunity cycle as a potential immunomodulator

xlomafota13 shared this article with you from Inoreader Nab-paclitaxel promotes the cancer-immunity cycle as a potential immunomodulator Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3445-3460. eCollection 2021. ABSTRACT Paclitaxel is a widely used anti-tumor chemotherapeutic drug. Solvent-based paclitaxel causes bone marrow suppression, allergic reactions, neurotoxicity and systemic toxicity, which are associated with non-specific cytotoxicity and side effects of fat-soluble solvents. Studies have explored various new nano-drug strategies of paclitaxel, including nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to improve the water solubility and safety of paclitaxel. Nab-paclitaxel is a targeted solvent-free formulation that inhibits microtubule depolymerization to anticancer. It is easily taken up by tumor and immune cells owing to the nano-scaled size and superior biocompatibility. The internalized nab-paclitaxel exhibits significant immunostimulatory activities to promote cancer-immunity cycle. The aim of this study was to explore the synergistic effect of nab-paclitaxe l in tumor antigen presentation, T cell activation, reversing the immunosuppressive pattern of tumor microenvironment (TME), and the synergistic effect with cytotoxic lymphocytes (CTLs) in clearance of tumor cells. The effects of nab-paclitaxel on modulation of cancer-immunity cycle, provides potential avenues for combined therapeutic rationale to improve efficacy of immunotherapy. PMID:34354854 | PMC:PMC8332864 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

MELD score is the better predictor for 30-day mortality in patients with ruptured hepatocellular carcinoma treated by trans-arterial embolization

xlomafota13 shared this article with you from Inoreader MELD score is the better predictor for 30-day mortality in patients with ruptured hepatocellular carcinoma treated by trans-arterial embolization Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3726-3734. eCollection 2021. ABSTRACT BACKGROUND AND AIMS: Spontaneous hepatocellular carcinoma (HCC) rupture is a catastrophic life-threatening complication that could be rescued by trans-arterial embolization (TAE). However, deteriorated liver function with total bilirubin more than 3 mg/dL was deemed as a relative contraindication. This study was aimed to re-evaluate this relative contraindication. METHODS: Patients with ruptured HCC and treated by TAE between February 2005 and December 2016 in Chang Gung Memorial Hospital, Linkou branch were recruited. Pre-TAE characteristics including age, gender, etiology, liver biochemistry, Child-Pugh classification, Model for End-Stage Liver Disease (MELD) score, the presence of shock, tumor staging and post TAE liver function were compared between patients with and without post-TAE 30-day mortality. RESULTS: A total of 186 patients were enrolled. The successful hemostatic rate after embolization was 91.4% and the median overall survival was 224 days. The 30-day cumulative mortality rate is 20.4%. By multivariate logistic regression analysis, male [aOR: 0.25, P=0.034] MELD score [aOR: 13.61, P<0.001], tumor size [aOR: 1.21, P=0.023] are the independent predictors for 30-day mortality. MELD score has better predictability of post-TAE 30-day mortality than total bilirubin level (AUROC: 0.818 vs. 0.668). The cut-off points of MELD score 13 has higher negative predictive value of 95% for post-TAE 30-day mortality. CONCLUSION: TAE is effective for the initial hemostasis in patients with HCC rupture. MELD score ≥13 rather than only total bilirubin level >3 mg/dL be more predictive of post TAE 30-day mortality. PMID:34354871 | PMC:PMC8332870 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

microRNA-196b promotes esophageal squamous cell carcinogenesis and chemoradioresistance by inhibiting EPHA7, thereby restoring EPHA2 activity

xlomafota13 shared this article with you from Inoreader microRNA-196b promotes esophageal squamous cell carcinogenesis and chemoradioresistance by inhibiting EPHA7, thereby restoring EPHA2 activity Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3594-3610. eCollection 2021. ABSTRACT Esophageal cancer (EC) is extremely aggressive and has a very poor survival rate. Esophageal squamous cell carcinoma (ESCC) accounts for 80% of all ECs worldwide, with the majority of the remaining 20% being esophageal adenocarcinoma (EAC). Due to its occult and insidious presentation, ESCC is typically diagnosed and treated in its advanced stages, thereby limiting the success of present therapeutic modalities. microRNAs (miRNAs) can function as tumor suppressors or oncogenes, playing critical roles in cancer initiation and progression by regulating target genes in oncogenic pathways. In the current study, we demonstrated that microRNA-196b (miR-196b) is one of the most upregulated miRNAs in both ESCC and EAC. miR-196b was overexpressed in ESCC and EAC cell lines, cellular exosomal RNAs, and ESCC tissue samples. Functional studies revealed that miR-196b acted as a n oncomiR by directly targeting a tumor suppressor, ephrin type-A receptor 7 (EPHA7). EPHA7 abrogates the activity of ephrin type-A receptor 2 (EPHA2), a key molecule involved in the epithelial-to-mesenchymal transition (EMT) and MAPK/ERK pathways, mediating resistance to UV and chemoradiotherapy in both ESCC and EAC. Taken together, these findings suggest that miR-196b is a strong candidate molecular target for EC treatment. PMID:34354862 | PMC:PMC8332861 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Doxycycline potentiates the anti-proliferation effects of gemcitabine in pancreatic cancer cells

xlomafota13 shared this article with you from Inoreader Doxycycline potentiates the anti-proliferation effects of gemcitabine in pancreatic cancer cells Via American Journal of Cancer Research Am J Cancer Res. 2021 Jul 15;11(7):3515-3536. eCollection 2021. ABSTRACT Gemcitabine is often recommended as a first-line treatment for patients with metastatic pancreatic cancer. However, gemcitabine resistance is a major challenge in the treatment of pancreatic ductal adenocarcinoma. Our group serendipitously identified the role of doxycycline as a potentiator of gemcitabine efficacy in pancreatic cancer cells. Doxycycline and gemcitabine co-treatment was significantly more cytotoxic to pancreatic cancer cells compared to gemcitabine alone. Interestingly, doxycycline only exerted synergistic effects when coupled with gemcitabine as opposed to other conventional chemotherapeutics including nucleoside analogs. The anti-clonogenic effects of gemcitabine on pancreatic cancer cells were also enhanced by doxycycline. According to cell cycle analyses, doxycycline prolonged gemcitabine-mediated S phase cell cycle arrest. Further, gene expres sion profiling analyses indicated that a small set of genes involved in cell cycle regulation were uniquely modulated by gemcitabine and doxycycline co-treatment compared to gemcitabine alone. Western blot analyses indicated that several cell cycle-related proteins, including cyclin D1, p21, and DNA damage inducible transcript 4 (DDIT4), were further modulated by doxycycline and gemcitabine co-treatment. Taken together, our findings indicate that doxycycline enhances the effects of gemcitabine on cell cycle progression, thus rendering pancreatic cancer cells more sensitive to gemcitabine. However, additional studies are required to assess the mechanisms of doxycycline and gemcitabine synergism, which might lead to novel treatment options for pancreatic cancer. PMID:34354858 | PMC:PMC8332860 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

131I-Labeled Multifunctional Polyethylenimine/Doxorubicin Complexes with pH-Controlled Cellular Uptake Property for Enhanced SPECT Imaging and Chemo/Radiotherapy of Tumors

xlomafota13 shared this article with you from Inoreader <sup>131</sup>I-Labeled Multifunctional Polyethylenimine/Doxorubicin Complexes with pH-Controlled Cellular Uptake Property for Enhanced SPECT Imaging and Chemo/Radiotherapy of Tumors Via radioactive iodine Int J Nanomedicine. 2021 Jul 30;16:5167-5183. doi: 10.2147/IJN.S312238. eCollection 2021. ABSTRACT INTRODUCTION: Smart theranostic nanosystems own a favorable potential to improve internalization within tumor while avoiding nonspecific interaction with normal tissues. However, development of this type of theranostic nanosystems is still a challenge. METHODS: In this study, we developed the iodine-131 (131I)-labeled multifunctional polyethylenimine (PEI)/doxorubicin (DOX) complexes with pH-controlled cellular uptake property for enhanced single-photon emission computed tomography (SPECT) imaging and chemo/radiotherapy of tumors. Alkoxyphenyl acylsulfonamide (APAS), a typical functional group that could achieve improved cellular uptake of its modified nanoparticles, was utilized to conjugate onto the functional PEI pre-modified with polyethylene glycol (PEG) with terminal groups of monomethyl ether and N-hydroxysuccinimide (mPEG-NHS), PEG with terminal groups of maleimide and succinimidyl valerate (MAL-PEG-SVA) through sulfydryl of APAS and MAL moiety of MAL-PEG-SVA. This was followed by conjugation with 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO), acetylating leftover amines of PEI, complexing DOX and labeling 131I to generate the theranostic nanosystems. RESULTS: The synthesized theranostic nanosystems exhibit favorable water solubility and stability. Every functional PEI can complex approximately 12.4 DOX, which could sust ainably release of DOX following a pH-dependent manner. Remarkably, due to the surface modification of APAS, the constructed theranostic nanosystems own the capacity to achieve pH-responsive charge conversion and further lead to improved cellular uptake in cancer cells under slightly acidic condition. Above all, based on the coexistence of DOX and radioactive 131I in the single nanosystem, the synthesized nanohybrid system could afford enhanced SPECT imaging and chemo/radioactive combination therapy of cancer cells in vitro and xenografted tumor model in vivo. DISCUSSION: The developed smart nanohybrid system provides a novel strategy to improve the tumor theranostic efficiency and may be applied for different types of cancer. PMID:34354350 | PMC:PMC8331118 | DOI:10.2147/IJN.S312238 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.