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WIREs Nanomed Nanobiotechnol
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Modifying the tumor microenvironment using nanoparticle therapeutics

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Treatment of cancer has come a long way from the initial ‘radical surgeries’ to the multimodality treatments. For the major part of the last century, cancer was considered as a monocellular disorder, and treatment strategies were designed according to that hypothesis. However, the mortality rate from cancer continued to be high and a comprehensive treatment remained elusive. Recent progress in research has demonstrated that tumors are a complex network of neoplastic and non‐neoplastic cells. The non‐neoplastic cells, which are collectively called stroma, assist in tumor survival and progression. It has been shown that disrupting the tumor‐stromal balance leads to significant effects on the tumor survival, and effective treatment can be achieved by targeting one or more of the stromal components. In this review, we summarize the roles of various stromal components in promoting tumor progression, and discuss innovative nanoparticle‐mediated drug targeting strategies for stromal depletion and the subsequent effects on the tumors. Perspectives and the future directions are also provided. WIREs Nanomed Nanobiotechnol 2016, 8:891–908. doi: 10.1002/wnan.1406 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Components of a tumor stroma. A complex network of neoplastic and non‐neoplastic cells constitute tumor stroma. A strong symbiotic relationship exists among them, which helps the tumor growth and survival. Just like an organ, tumor has its own support cells, blood vessels, residing immune cells, and even stem cells that help its survival and propagation.
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Combined chemoimmunotherapy using a nanoparticle co‐encapsulating a cytotoxic drug (paclitaxel) and a TLR4 agonist (P‐LPS). The cytotoxic drug kills and debulks the tumor as well as produces tumor antigens due to apoptotic tumor cell death. The TLR4 agonist activates the macrophages to the M1 subtype which then present the tumor antigens as well as secrete cytokines to activate cytotoxic T cells, producing a potent antitumor Th1 immune response. (Reprinted with permission from Ref Copyright 2013 Elsevier)
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Proposed mechanism for Cellax intracellular internalization. Cellax adsorbs albumin in circulation and accumulated within the tumor interstitium through the leaky vasculature of the tumor. Secreted protein acidic and rich in cysteine (SPARC) produced in the tumor microenvironment binds to the surface albumin on the Cellax nanoparticles and thus traps the particles in the tumor. Cellax is internalized via a clathrin‐mediated mechanism and finally ends up in the endolysosomal compartment, where the polymer is broken down and the drug is released. (Reprinted with permission from Ref . Copyright 2015 Elsevier)
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(a) Colocalization of Cellax nanoparticles with α‐smooth muscle actin (α‐SMA)+ cancer‐associated fibroblast (CAF) cells (green: α‐SMA; red: Cellax‐DiI; blue: DAPI). (b–e) Effects of native docetaxel (DTX), nab‐paclitaxel (nab‐PTX), and Cellax on the CAF cells in different orthotopic breast cancer models [4T1 (b, c) and MDA‐MB‐231 (d, e)]. Treatment with Cellax leads to marked reduction in the α‐SMA+ CAF cells in both of the models. (Reprinted with permission from Ref . Copyright 2013 American Association for Cancer Research; from Ref . Copyright 2015 Elsevier)
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Tumor‐associated macrophage (TAM)—recruitment, transformation, and activity. Owing to secretion of different factors (CCL‐2, M‐CSF) from the tumor stroma, monocytes accumulate at the tumor microenvironment (TME). Owing to the primarily immunosuppressive nature of TME, these monocytes differentiate into M2 phenotype. M2 macrophages assist tumor survival and metastasis as well as downregulate immune response at the TME by secretion of different cytokines.
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Tumor angiogenesis and metastasis. Tumor cells proliferate rapidly and have a high metabolic demand. To fulfill their energy requirements, tumor cells and other stromal cells produce different angiogenic factors including vascular endothelial growth factor (VEGF), which activates the endothelial cells and stimulates proliferation. Tumor stroma also produce a host of proteases and matrix metalloproteinases (MMPs) that help basement membrane remodeling. Following the breakdown of basement membrane, proliferating endothelial cells lead to uncontrolled neovascularization. These newly formed vessels are irregular and leaky, through which tumor cells escape and metastasize to distant organs.
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Effect of cancer‐associated fibroblasts (CAF) on tumor and other stromal cells. CAFs can promote tumorigenesis directly through multiple mechanisms, including increased angiogenesis, proliferation, invasion, and inhibition of tumor cell death. These effects are mediated through the expression and secretion of numerous growth factors, cytokines, proteases, and extracellular matrix proteins.
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