The Tumor Microenvironment (Cancer Drug Discovery and Development)

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Please enable JavaScript to access the full features of the site or access our non-JavaScript page. Issue 3, The xenograft mouse model is the most commonly used preclinical model for evaluating the efficacy of anticancer drugs. Xenograft models are established by implanting human cancer cells into heterogeneous mouse tissues such as human brain cancer cells to subcutaneous tissue, which is termed heterotopic or into the same tissue origin such as the implantation of human brain cancer cells to the mouse brain, which is termed orthotopic Although this in vivo xenograft model has revolutionized the drug discovery process, it does not reflect the human tumor microenvironment such as the immune response because of the utilization of immunocompromised mice A more advanced model, patient-derived tumor xenograft PDX , has been developed The PDX model utilizes patient-derived primary cancer cells when establishing in vivo models; therefore, this model better reflects patient-specific drug responses, showing the possibility to be used in personalized medicine However, the PDX model also has several unresolved limitations such as a time-consuming process and high cost To overcome the limitations of in vivo mouse models, researchers in biomedical engineering have been working on the development of more in vivo -like models.

By developing more physiologically relevant models and using them in the drug discovery process, drug screening speed and efficiency will increase, and developmental costs will decrease. There are additional issues in the development of physiologically relevant in vitro platforms.

First, high-throughput screening ability is required for testing large numbers of drug candidates. In the initial stages of drug screening, different concentrations of thousands of drug candidates are tested on various cancer cell types with different genetic mutations. Thus, the number of combinations is so large that high-throughput screening becomes a critical need.

Manipulating the Tumor Microenvironment: Opportunities for Therapeutic Targeting | Bentham Science

To address this issue, pharmaceutical companies have been employing well plate-based assays using or well plates; however, these platforms only provide a two-dimensional, static environment. Recently developed technologies such as patterned spheroid arrays are believed to resolve this high-throughput screening issue without sacrificing the physiological features of the tumor microenvironment. The second issue is the development of precision medicine or patient-specific drugs. Recent strategies of pharmaceutical companies include targeting specific genetic mutations, signaling pathways, cytokines, and enzymes with target-specific antibodies.

Since the therapeutic effect of a single drug or drug cocktail depends on the individual patient characteristics, the identification of an effective agent in an in vitro model prepared using patient-derived cells is a promising approach for the development of targeted treatments.

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The organ-on-a-chip, an organoid made of patient-derived iPS, and PDX models can be useful for this strategy. However, in some models, the time required to establish a platform is so long that a more innovative approach with reduced process time is critical for the effective treatment of patients. Third, the acquisition of patient-derived cells and the establishment of reliable cell lines are also important issues in the development of physiologically relevant in vitro models To address the advancement of antibody-based chemotherapy, cancer cells expressing specific ligands and activated signaling pathways are needed to test the efficacy of newly developed drugs.

However, the limited availability of patient-derived cells for use in precision medicine and the stable cell lines for high-throughput screening hinders the development of in vitro models. In addition to that of cancer cells, the availability of patient-derived stromal cells is also essential because of their largely unknown regulatory mechanisms Finally, including multiple environmental factors in a single platform is also an unmet need.

Although the effects of individual factors, such as ECM, flow, pH, and hypoxia, have been investigated, their synergistic role remains largely unknown. In stem cell research, stem cell differentiation is synergistically enhanced when multiple cues are provided simultaneously , These results imply that the tumor cells might also be synergistically affected by the environmental factors because of their inherent complexity. Therefore, such synergistic effect of multiple environmental factors on cancer progression and chemoresistance needs to be investigated.

In particular, the interaction between cancer and stromal cells is largely unknown because of the limited number of available cell sources and analysis techniques. It is expected that more reliable in vitro cancer models will be developed in the future because of the advancement of engineering techniques and the abundance of cell sources. These advanced platforms can revolutionize the drug discovery process.

In this article, we have summarized the recent advances in the development of drug screening models, specifically those used to study the efficacy of anti-cancer drug candidates. We first gave an overview of the characteristics of the tumor microenvironment in terms of physical and biochemical properties including hypoxia, pH, interstitial flow, cell-cell and cell-matrix interactions.

Next, we discussed engineered platforms that attempted to reproduce these environmental factors. Finally, the changes in the cytotoxicity of anti-cancer drugs in response to the engineered environmental factors were summarized. Several studies comparing the cytotoxicity of different anti-cancer drugs have shown that drug efficacy is strongly influenced by the culture conditions of the cancer cells.

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  2. The Measure of Manhattan: The Tumultuous Career and Surprising Legacy of John Randel, Jr., Cartographer, Surveyor, Inventor.
  3. Ex Vivo Engineering of the Tumor Microenvironment.
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  5. Cancer Drug Discovery and Development: The Tumor Microenvironment (2010, Hardcover).
  6. However, the current technologies do not fully mimic the complex microenvironment of the tumor because of the limited availability of fabrication techniques, biomaterials, and cell sources. If the in vitro cancer models can mimic the in vivo physiology more closely, the efficacy and toxicity of drug candidates can be gauged accurately. National Center for Biotechnology Information , U. Journal List Theranostics v. Published online Oct Author information Article notes Copyright and License information Disclaimer. Hong Nam Kim, Email: rk. Jonghoon Choi, Email: rk.

    The tumor microenvironment controls drug sensitivity

    Received Aug 8; Accepted Oct 4. This article has been cited by other articles in PMC. Abstract For decades, scientists have been using two-dimensional cell culture platforms for high-throughput drug screening of anticancer drugs. Keywords: chemoresistance, tumor microenvironment, cancer cell, biomimetic, efficacy.

    Open in a separate window. Figure 1. Physiology of the TME and its effect on drug delivery and efficacy The TME comprises multiple cellular and noncellular components organized in a three-dimensional form 25 , Figure 2. Table 1 The tumor environmental factors that affect the efficacy of anti-cancer drugs. Tumor microenvironmental factors Mechanism Results Ref. Physical cues The physical components of the TME can affect the sensitivity of tumor cells to drugs.

    Biological and biochemical cues The uncontrolled growth of cancer cells generates densely packed cell spheroids.

    Biomimetic platforms that replicate the physiology of the TME In this section, recent approaches that mimic the TME using the engineered platforms are overviewed. Tumor spheroids Tumor spheroids have been one of the widely used 3D models for cancer study. Figure 3. Microfluidic cell culture systems Microfluidics refers to the technology that allows the manipulation of tiny amounts 10 -9 to 10 liters of fluids using channels with specific dimensions on the order of tens to hundreds of micrometers Figure 4.

    Polymeric scaffolds The physical structure of the ECM in the TME plays a crucial role in regulating various cancer cell behaviors such as growth, proliferation, tumor invasion, transformation, and drug response in a number of cell types 48 , - Figure 5. Perspective and Conclusion Out of every few thousands of drug candidates screened and tested, very few drugs are approved for clinical use. References 1. Hanahan D. Rethinking the war on cancer. Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Bio. Targeting the tumour vasculature: insights from physiological angiogenesis.

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    Microfluidic modelling of the tumor microenvironment for anti-cancer drug development

    Nat Rev Drug Discov.