The use of nanomedicine for cancer treatment takes advantage of its preferential accumulation in tumors owing to the enhanced permeability and retention (EPR) effect. The development of cancer nanomedicine has promised highly effective treatment options unprecedented by standard therapeutics. However, the therapeutic efficacy of passively targeted nanomedicine is not always satisfactory because it is largely influenced by the heterogeneity of the intensity of the EPR effect exhibited within a tumor, at different stages of a tumor, and among individual tumors. In addition, limited data on EPR effectiveness in human hinders further clinical translation of nanomedicine. This unsatisfactory therapeutic outcome in mice and humans necessitates novel approaches to improve the EPR effect. This review focuses on current attempts at overcoming the limitations of traditional EPR-dependent nanomedicine by incorporating supplementary strategies, such as additional molecular targeting, physical alteration, or physiological remodeling of the tumor microenvironment. This review will provide valuable insight to researchers who seek to overcome the limitations of relying on the EPR effect alone in cancer nanomedicine and go "beyond the EPR effect".

Alliance with EPR Effect: Combined Strategies to Improve the EPR Effect in the Tumor Microenvironment.

Nanoparticles for modulating tumor microenvironment to improve drug delivery and tumor therapy.

Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment

Cancer remains as one of the leading cause of death worldwide. The development of cancer involves an intricate process, wherein many identified and unidentified factors play a role. Although most studies have focused on the genetic abnormalities which initiate and promote cancer, there is overwhelming evidence that tumors interact within their environment by direct cell-to-cell contact and with signaling molecules, suggesting that cancer cells can influence their microenvironment and bidirectionally communicate with other systems. However, only in recent years the role of the nervous system has been recognized as a major contributor to cancer development and metastasis. The nervous system governs functional activities of many organs, and, as tumors are not independent organs within an organism, this system is integrally involved in tumor growth and progression.

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Role of the nervous system in cancer metastasis.

Parameters Affecting the Enhanced Permeability and Retention Effect: The Need for Patient Selection

Enhancing chemotherapy delivery to tumors, improving tumor growth control, reducing metastasis, and increasing survival are all critical objectives of improved cancer therapy. One of the obstacles to the success of anticancer therapies is related to the inefficient distribution of drugs to tumor cells. To be effective, chemotherapeutics must reach a concentration in cancer cells that is sufficient to inhibit its targets. In the past years, the vascular normalization theory has gained widespread acceptance for explaining additional antitumor effects of inhibitors of vascular endothelial growth factor (VEGF) signaling, when combined with chemotherapeutics. Vascular normalization is a strategy to enhance the antitumor effects of chemotherapeutics, but this is time and dose dependent and therefore difficult to implement clinically. Thus, alternative strategies that overcome these issues are needed. Accumulating scientific data demonstrate an alternative approach called "vascular promotion therapy" can increase chemotherapeutics delivery and intracellular uptake of the drug and reduces hypoxia by increasing tumor blood vessel density, blood flow, leakiness, and dilation, which leads to reduced cancer growth and metastasis. In this article, we first summarize the structural and functional abnormalities of the tumor microvasculature to highlight the importance of this phenomenon for chemotherapeutics distribution. Next, we summarize the limitations of anti-angiogenic strategy in cancer treatment, discuss some key prototypical underlying mechanisms of vascular normalization and initial clinical evidence of vascular promotion therapy, and speculate on the clinical potential of anticoagulation as a novel paradigm to improve cancer treatment.

Anti-angiogenesis or pro-angiogenesis for cancer treatment: focus on drug distribution.

Background
Epidemiologic evidence suggests that chronic inflammation and/or chronic infection is associated with cancer development, and the inflammatory process may play a crucial role in the carcinogenesis and prognosis of colorectal cancer (CRC). Substance P (SP) belongs to the family of tachykinins and acts as an immunomodulator, binding to the neurokinin-1 receptor (NK1R) to initiate tumor cell proliferation, angiogenesis, and migration, steps that are critical for tumor cell invasion and metastasis. It is suggested that SP/NK1R signaling may play an important role in cancer progression and metastasis. However, the exact involvement and significance of SP and NK1R in CRC pathologies remain to be adequately deciphered.

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High expression of substance P and its receptor neurokinin-1 receptor in colorectal cancer is associated with tumor progression and prognosis

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising result in cancer therapy and induces apoptosis in a wide variety of tumor cells, without causing toxicity to normal cells However, many tumor cells including acute myeloid leukemia (AML) showed certain degrees of resistance to TRAIL and the mechanism remains largely unknown Embelin is a potent XIAP inhibitor which has been shown to inhibit the proliferation of tumor cells and cause cell apoptosis In this study, we investigated the effects of Embelin on the TRAIL-induced apoptosis and the underlying mechanism Here, we chose an adenovirus vector as the expression vector for TRAIL, which was named Ad-TRAIL The results in vitro showed that the co-treatment of Embelin and Ad-TRAIL has synergistically suppressed the proliferation of AML cells Embelin has the ability to enhance TRAIL-induced apoptosis and activate caspase pathway More interestingly, we found that the underlying mechanism for these talent skills of Embelin is through reducing the TRAIL-mediated activation of NF-κB and decreasing its transcriptional activity Furthermore, our results in vivo suggest that combined therapy of Embelin and Ad-TRAIL caused significant growth inhibition of HL-60 xenograft tumors Our results suggested that Embelin could sensitize AML cell to TRAIL through the repression of NF-κB signal pathway in vitro and in vivo, and combined therapy of Ad-TRAIL and Embelin may be the attractive candidate for clinical application in treatment of AML

Embelin sensitizes acute myeloid leukemia cells to TRAIL through XIAP inhibition and NF-κB inactivation

With no effective treatments available for most pancreatic cancer patients, pancreatic cancer continues to be one of the most difficult malignancies to treat. Oncolytic virus mediated-gene therapy has exhibited ubiquitous antitumor potential. In this study, we constructed a novel oncolytic vaccinia virus harboring the inhibitor of growth family member 4 gene (VV-ING4) to investigate its therapeutic efficacy alone or in combination with gemcitabine against pancreatic cancer cells in vitro and in vivo. ING4 expression was determined via quantitative real-time polymerase chain reaction (qPCR) and western blot. The cytotoxicity of VV-ING4 was measured using a cell proliferation assay. Both flow cytometry and western blot were applied to analyze the cell cycle and apoptosis. Furthermore, the combination inhibitory effect of VV-ING4 and gemcitabine was assessed using Chou-Talalay analysis in vitro and a BLAB/c mice model in vivo. We found that VV-ING4 significantly increases ING4 expression, displayed greater cytotoxic efficiency, and induced pancreatic cancer cell apoptosis and G2/M phase arrest. Additionally, the combination of VV-ING4 and gemcitabine synergistically effect in vitro and in vivo. Taken together, our data implicate VV-ING4 as a conceivable pancreatic cancer therapeutic candidate alone or in combination with gemcitabine.

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Shibing Wang

Papers

Anti-angiogenesis or pro-angiogenesis for cancer treatment: focus on drug distribution.

High expression of substance P and its receptor neurokinin-1 receptor in colorectal cancer is associated with tumor progression and prognosis

Embelin sensitizes acute myeloid leukemia cells to TRAIL through XIAP inhibition and NF-κB inactivation

ING4 expressing oncolytic vaccinia virus promotes anti-tumor efficiency and synergizes with gemcitabine in pancreatic cancer.