Hypoxic tumor microenvironment: Opportunities to develop targeted therapies

Patel, Akhil; Sant, Shilpa

doi:10.1016/j.biotechadv.2016.04.005

Cited by 170 publications

(124 citation statements)

References 107 publications

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“…For example, a layer-by-layer pH-responsive sheddable nanoparticle shell exists in which the neuronal layers that encapsulate the drug are only shed in response to the low pH in the tumor, exposing the nanoparticle surface loaded with a chemotherapeutic agent that can be taken up by the cells (Poon et al 2011). Similarly, the hypoxic regions of the tumor have been leveraged to optimize therapeutic delivery to tumor regions using multiple mechanisms (Patel and Sant 2016). One such example is provided by a bioactive prodrug, such as the Noxide drug tirapazamine (TPZ), which induces DNA damage, works synergistically with chemotherapy and radiation therapy, and is only activated under hypoxia (von Pawel et al 2000).…”

Section: Taking Advantage Of the Gradientmentioning

confidence: 99%

Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

Oudin

Weaver

2016

Cold Spring Harb Symp Quant Biol

149

121

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Cancer metastasis requires the invasion of tumor cells into the stroma and the directed migration of tumor cells through the stroma toward the vasculature and lymphatics where they can disseminate and colonize secondary organs. Physical and biochemical gradients that form within the primary tumor tissue promote tumor cell invasion and drive persistent migration toward blood vessels and the lymphatics to facilitate tumor cell dissemination. These microenvironment cues include hypoxia and pH gradients, gradients of soluble cues that induce chemotaxis, and ions that facilitate galvanotaxis, as well as modifications to the concentration, organization, and stiffness of the extracellular matrix that produce haptotactic, alignotactic, and durotactic gradients. These gradients form through dynamic interactions between the tumor cells and the resident fibroblasts, adipocytes, nerves, endothelial cells, infiltrating immune cells, and mesenchymal stem cells. Malignant progression results from the integrated response of the tumor to these extrinsic physical and chemical cues. Here, we first describe how these physical and chemical gradients develop, and we discuss their role in tumor progression. We then review assays to study these gradients. We conclude with a discussion of clinical strategies used to detect and inhibit these gradients in tumors and of new intervention opportunities. Clarifying the role of these gradients in tumor evolution offers a unique approach to target metastasis.Tumors are highly heterogeneous and this feature compromises treatment efficacy and promotes tumor cell dissemination and metastasis to reduce patient survival. Tumor heterogeneity is driven in part by genetic alterations induced through genomic instability and maintained by the evolutionary selection of these genetically modified cells (Alizadeh et al. 2015). Epigenetic, transcriptional, and posttranslational modifications also contribute significantly to tumor cell diversity. Furthermore, cancer develops within a complex tissue microenvironment that itself fosters tumor heterogeneity through clonal selection as well as via epigenetic reprogramming and modifications of the tumor phenotype. The tumor microenvironment is composed of cellular constituents that include cells of the vasculature, infiltrating immune cells, and resident fibroblasts, adipocytes and nerves, and a noncellular component composed of diverse soluble factors and a highly variable and evolving insoluble extracellular matrix (ECM) (Joyce and Pollard 2009). The composition and organization of the tumor microenvironment vary significantly within and across tumors.One key feature of the noncellular microenvironment is the existence of local chemical and physical gradients that exert profound effects on the tumor phenotype, including its predilection to disseminate. In this regard, metastasis is facilitated by efficient local tumor cell invasion that is fostered by ECM and chemokine/cytokine/growth factor gradients which cooperate to promote the directional migration of the t...

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Section: Taking Advantage Of the Gradientmentioning

confidence: 99%

Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

Oudin

Weaver

2016

Cold Spring Harb Symp Quant Biol

149

121

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“…Inflammation can promote tumor development by angiogenesis and organization restructuring (2). Inflammatory microenvironment is major structure of all the tumors (14). About 90% of tumor are related with mutation of somatic cell and environment factor.…”

Section: Discussionmentioning

confidence: 99%

Endostatin reverses immunosuppression of the tumor microenvironment in lung carcinoma

et al. 2017

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Abstract.Endostatin has previously been demonstrated to efficiently inhibit the angiogenesis and growth of endothelial cells. However, the role of endostatin in the tumor microenvironment remains to be elucidated. To investigate the antitumor effect of endostatin in lung cancer, the present study was designed to explore the alterations of microvessel density in Lewis lung cancer models and the expression of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-17, interferon (IFN)-γ and hypoxia inducible factor (HIF)-1α, following endostatin therapy. It was demonstrated that the growth and angiogenesis of tumors were markedly suppressed by treatment with endostatin, compared with control group. The microvessel density in mice treated with endostatin was significantly inhibited in a dose-dependent manner. The expression levels of VEGF, IL-6 and IL-17 in tumors were decreased, however IFN-γ and HIF-1α expression levels were increased, following treatment with endostatin. In addition, the proportion of myeloid derived suppressor cells and tumor associated macrophages (TAMs; M2 type) were significantly decreased, whereas those of mature dendritic cells and TAMs (M1 type) were increased, and cluster of differentiation (CD)8 + T cells were recruited to infiltrate the tumors following treatment with endostatin. In addition, the expression levels of IL-6, IL-10, tumor growth factor-β and IL-17 in tumor tissue were potently decreased with endostatin therapy. These results indicated that endostatin efficiently inhibited tumor angiogenesis and reversed the immunosuppressive microenvironment associated with the presence of tumors.

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“…at/cgi‐bin/RNAfold.cgi). The criteria for secondary structure prediction were: number of nucleotides in one bulge in stem (≤12) number of base pairs in the stem region of the predicted hairpin (≥16) cutoff of free energy (kCal/mol ≤−15) length of hairpin (top and bottom stems + terminal loop ≥50) length of hairpin loop (≤20) number of nucleotides in one bulge in mature region (≤8) number of biased errors in one bulge in mature region (≤4) number of biased bulges in mature region (≤2) number of errors in mature region (≤ 7) number of base pairs in the mature region of the predicted hairpin (≥ 12) percent of mature in stem (≥80).…”

Section: Methodsmentioning

confidence: 99%

“…The tumor microenvironment (TME) is made up of different cell types, extracellular matrix, and numerous extracellular molecules . Accumulated evidence underscores the role of TME in promoting tumor formation and progression . Hypoxia is a phenomenon commonly observed in the TME and is defined as the reduction in tissue oxygen tension .…”

Section: Introductionmentioning

confidence: 99%

“…Accumulated evidence underscores the role of TME in promoting tumor formation and progression . Hypoxia is a phenomenon commonly observed in the TME and is defined as the reduction in tissue oxygen tension . Several cancer characteristics, such as neovascularization, alteration of energy metabolism, immune escape, initiation of invasion and metastasis, uncontrolled inflammation, sustaining proliferation, repressing apoptosis, and genomic instability are associated with hypoxia …”

Section: Introductionmentioning

confidence: 99%

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Hypoxia induced changes in miRNAs and their target mRNAs in extracellular vesicles of esophageal squamous cancer cells

Chen

Chu

et al. 2020

Thoracic Cancer

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Background Extracellular vesicles (EVs) are endogenous membrane vesicles with a diameter of 30–200 nm. It has been reported that hypoxic cancer cells can release numerous EVs to mediate multiple regional and systemic effects in the tumor microenvironment. Methods In this study, we used ultracentrifugation to extract EVs secreted by TE‐13, an esophageal squamous carcinoma (ESCC) cell line during normoxia and hypoxia and performed high‐throughput sequencing to detect exosomal miRNAs. Gene ontology (GO) and KEGG pathway analyses were used to reveal pathways potentially regulated by the miRNAs. Results A total of 10 810 miRNAs were detected; 50 were significantly upregulated and 34 were significantly downregulated under hypoxic environment. GO analysis identified enrichment of protein binding, regulation of transcription (DNA‐templated), and membrane as molecular function, biological process, and cellular component, respectively. KEGG pathway analysis revealed cancer‐associated pathways, phospholipase D signaling pathway, autophagy, focal adhesion and AGE‐RAGE signaling as the key pathways. Further verification experiment from qRT‐PCR indicated that miR‐128‐3p, miR‐140‐3p, miR‐340‐5p, miR‐452‐5p, miR‐769‐5p and miR‐1304‐p5 were significantly upregulated in EVs from hypoxia TE‐13 cells while miR‐340‐5p was significantly upregulated in two other ESCC cells, ECA109 and TE‐1. Conclusion This study, for the first time reveals changes in the expression of exosomal miRNAs in hypoxic ESCC cells and these findings will act as a resource to study the hypoxic tumor microenvironment and ESCC EVs.

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Hypoxic tumor microenvironment: Opportunities to develop targeted therapies

Cited by 170 publications

References 107 publications

Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

Endostatin reverses immunosuppression of the tumor microenvironment in lung carcinoma

Hypoxia induced changes in miRNAs and their target mRNAs in extracellular vesicles of esophageal squamous cancer cells

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