Angiogenesis is the process through which novel blood vessels are formed from pre-existing ones and it is involved in both physiological and pathological processes of the body. Furthermore, tumor angiogenesis is a crucial factor associated with tumor growth, progression, and metastasis. In this manner, there has been a great interest in the development of anti-angiogenesis strategies that could inhibit tumor vascularization. Conventional approaches comprise the administration of anti-angiogenic drugs that target and block the activity of proangiogenic factors. However, as their efficacy is still a matter of debate, novel strategies have been focusing on combining anti-angiogenic agents with chemotherapy or immunotherapy. Moreover, nanotechnology has also been investigated for the potential of nanomaterials to target and release anti-angiogenic drugs at specific sites. The aim of this paper is to review the mechanisms involved in angiogenesis and tumor vascularization and provide an overview of the recent trends in anti-angiogenic strategies for cancer therapy.

Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment

It is now well known that non-coding RNAs (ncRNAs), rather than protein-coding transcripts, are the preponderant RNA transcripts. NcRNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation, apoptosis, invasion, metastasis, and genomic instability. Despite recent discoveries in cancer therapy, resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy continue to be a major setback. Recent studies have shown that ncRNAs also play a major role in resistance to different cancer therapies by rewiring essential signaling pathways. In this review, we present the intricate mechanisms through which dysregulated ncRNAs control resistance to the four major types of cancer therapies. We will focus on the current clinical implications of ncRNAs as biomarkers to predict treatment response (intrinsic resistance) and to detect resistance to therapy after the start of treatment (acquired resistance). Furthermore, we will present the potential of targeting ncRNA to overcome cancer treatment resistance, and we will discuss the challenges of ncRNA-targeted therapy-especially the development of delivery systems. 

/pdf/targeting-non-coding-rnas-to-overcome-cancer-therapy-1zf2ga0l.pdf

Targeting non-coding RNAs to overcome cancer therapy resistance

Epithelial-to-mesenchymal transition (EMT) is implicated in a wide array of malignant behaviors of cancers, including proliferation, invasion, and metastasis. Most notably, previou studies have indicated that both cancer stem-like properties and drug resistance were associated with EMT. Furthermore, microRNAs (miRNAs) play a pivotal role in the regulation of EMT phenotype, as a result, some miRNAs impact cancer stemness and drug resistance. Therefore, understanding the relationship between EMT-associated miRNAs and cancer stemness/drug resistance is beneficial to both basic research and clinical treatment. In this review, we preliminarily looked into the various roles that the EMT-associated miRNAs play in the stem-like nature of malignant cells. Then, we reviewed the interaction between EMT-associated miRNAs and the drug-resistant complex signaling pathways of multiple cancers including lung cancer, gastric cancer, gynecologic cancer, breast cancer, liver cancer, colorectal cancer, pancreatic cancer, esophageal cancer, and nasopharyngeal cancer. We finally discussed the relationship between EMT, cancer stemness, and drug resistance, as well as looked forward to the potential applications of miRNA therapy for malignant tumors.

EMT-associated microRNAs and their roles in cancer stemness and drug resistance.

Therapy resistance is a characteristic of cancer cells that significantly reduces the effectiveness of drugs. Despite the popularity of cisplatin (CP) as a chemotherapeutic agent, which is widely used in the treatment of various types of cancer, resistance of cancer cells to CP chemotherapy has been extensively observed. Among various reported mechanism(s), the epithelial–mesenchymal transition (EMT) process can significantly contribute to chemoresistance by converting the motionless epithelial cells into mobile mesenchymal cells and altering cell–cell adhesion as well as the cellular extracellular matrix, leading to invasion of tumor cells. By analyzing the impact of the different molecular pathways such as microRNAs, long non-coding RNAs, nuclear factor-κB (NF-ĸB), phosphoinositide 3-kinase-related protein kinase (PI3K)/Akt, mammalian target rapamycin (mTOR), and Wnt, which play an important role in resistance exhibited to CP therapy, we first give an introduction about the EMT mechanism and its role in drug resistance. We then focus specifically on the molecular pathways involved in drug resistance and the pharmacological strategies that can be used to mitigate this resistance. Overall, we highlight the various targeted signaling pathways that could be considered in future studies to pave the way for the inhibition of EMT-mediated resistance displayed by tumor cells in response to CP exposure.

https://www.mdpi.com/1422-0067/21/11/4002/pdf

Association of the Epithelial-Mesenchymal Transition (EMT) with Cisplatin Resistance.

Targeting tumor microenvironment in ovarian cancer: Premise and promise.

Summary Background Anti-angiogenic therapy combined with chemotherapy could improve the outcomes of patients with platinum-resistant ovarian cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and oral etoposide, considering the potential advantage of home administration without hospital admission, in patients with platinum-resistant or platinum-refractory ovarian cancer. Methods In this phase 2, single-arm, prospective study, we recruited patients aged 18–70 years with platinum-resistant or platinum-refractory ovarian cancer at the Sun Yat-sen University Cancer Center (China). The treatment consisted of apatinib at an initial dose of 500 mg once daily on a continuous basis, and oral etoposide at a dose of 50 mg once daily on days 1–14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1. We used Simon's two-stage design, and analysed efficacy in the intention-to-treat and per-protocol populations. Safety analyses included enrolled patients who had received at least one dose of study medication, but excluded those without any safety data. This study is registered with ClinicalTrials.gov , number NCT02867956 . Findings Between Aug 10, 2016, and Nov 9, 2017, we screened 38 and enrolled 35 patients. At the data cutoff date (Dec 31, 2017), 20 (57%) patients had discontinued the study, and 15 (43%) patients remained on treatment. Objective responses were achieved in 19 (54%; 95% CI 36·6–71·2) of 35 patients in the intention-to-treat population and in 19 (61%; 42·2–78·2) of 31 patients in the per-protocol population. The most common grade 3 or 4 adverse events were neutropenia (17 [50%]), fatigue (11 [32%]), anaemia (ten [29%]), and mucositis (eight [24%]). Serious adverse events were reported in two patients who were admitted to hospital (one patient had anaemia and anorexia; the other patient had increased ascites due to disease progression). No treatment-related deaths were recorded. Interpretation The combination of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory ovarian cancer, and further study in phase 3 trials is warranted. Funding None.

Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study

Epithelial–mesenchymal transition (EMT) and dysregulated microRNAs (miRNAs) have important roles in driving chemoresistance. We previously reported that iASPP is a key EMT inducer and could increase cisplatin resistance in cervical cancer (CC) cells. Herein, we investigate the downstream mechanisms through which iASPP contributes to EMT and cisplatin resistance in CC. By using a lentiviral system, we investigated the effects of iASPP knockdown on CC cell growth and chemosensitivity of CC cells to cisplatin in vivo. We examined if miR-20a, which was up-regulated following iASPP overexpression, would influence metastatic phenotypes and cisplatin resistance in CC cells, and explored the possible molecular mechanisms involved. Knockdown of iASPP suppressed CC cell proliferation and sensitized CC cells to cisplatin in vivo. iASPP promotes miR-20a expression in a p53-dependent manner. Upregulation of miR-20a induced EMT and the recovery of CC cell invasion and cisplatin chemoresistance that was repressed by iASPP knockdown. We identified FBXL5 and BTG3 as two direct miR-20a targets. Silencing of FBXL5 and BTG3 restored cell invasion and cisplatin chemoresistance, which was suppressed by iASPP or miR-20a knockdown. Reduced FBXL5 and BTG3 expression was found in CC samples and associated with poor prognosis in CC patients. iASPP promotes EMT and confers cisplatin resistance in CC via miR-20a-FBXL5/BTG3 signaling.

/pdf/iaspp-induces-emt-and-cisplatin-resistance-in-human-cervical-49k7gvpxdy.pdf

iASPP induces EMT and cisplatin resistance in human cervical cancer through miR-20a-FBXL5/BTG3 signaling.

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Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study

iASPP induces EMT and cisplatin resistance in human cervical cancer through miR-20a-FBXL5/BTG3 signaling.