The complex microenvironment in which malignant tumor cells grow is crucial for cancer progression. The physical and biochemical characteristics of this niche are involved in controlling cancer cell differentiation, proliferation, invasion, and metastasis. It is therefore essential to understand how cancer cells interact and communicate with their surrounding tissue – the so-called tumor stroma – and how this interplay regulates disease progression. To mimic the tumor microenvironment (TME), 3D in vitro models are widely used because they can incorporate different patient-derived tissues/cells and allow longitudinal readouts, thus permitting deeper understanding of cell interactions. These models are therefore excellent tools to bridge the gap between oversimplified 2D systems and unrepresentative animal models. We present an overview of state-of-the-art 3D models for studying tumor–stroma interactions, with a focus on understanding why the TME is a key target in cancer therapy.

3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions

https://www.nature.com/articles/s43586-022-00118-6.pdf

A guide to the organ-on-a-chip

Organs-on-chips (OoCs) are systems containing engineered or natural miniature tissues grown inside microfluidic chips. To better mimic human physiology, the chips are designed to control cell microenvironments and maintain tissue-specific functions. Combining advances in tissue engineering and microfabrication, OoCs have gained interest as a next-generation experimental platform to investigate human pathophysiology and the effect of therapeutics in the body. There are as many examples of OoCs as there are applications, making it difficult for new researchers to understand what makes one OoC more suited to an application than another. This Primer is intended to give an introduction to the aspects of OoC that need to be considered when developing an application-specific OoC. The Primer covers guiding principles and considerations to design, fabricate and operate an OoC, as well as subsequent assaying techniques to extract biological information from OoC devices. Alongside this is a discussion of current and future applications of OoC technology, to inform design and operational decisions during the implementation of OoC systems. Organs-on-chips are microfluidic systems containing miniature tissues with the aim of mimicking human physiology for a range of biomedical and therapeutic applications. Leung, de Haan et al. report practical tips to inform design and operational decisions during the implementation of organ-on-a-chip systems. 

Lung cancer is a main cause of death all over the world with a high incidence rate. Metastasis into neighboring and distant tissues as well as resistance of cancer cells to chemotherapy demand novel strategies in lung cancer therapy. Curcumin is a naturally occurring nutraceutical compound derived from Curcuma longa (turmeric) that has great pharmacological effects, such as anti-inflammatory, neuroprotective, and antidiabetic. The excellent antitumor activity of curcumin has led to its extensive application in the treatment of various cancers. In the present review, we describe the antitumor activity of curcumin against lung cancer. Curcumin affects different molecular pathways such as vascular endothelial growth factors, nuclear factor-κB (NF-κB), mammalian target of rapamycin, PI3/Akt, microRNAs, and long noncoding RNAs in treatment of lung cancer. Curcumin also can induce autophagy, apoptosis, and cell cycle arrest to reduce the viability and proliferation of lung cancer cells. Notably, curcumin supplementation sensitizes cancer cells to chemotherapy and enhances chemotherapy-mediated apoptosis. Curcumin can elevate the efficacy of radiotherapy in lung cancer therapy by targeting various signaling pathways, such as epidermal growth factor receptor and NF-κB. Curcumin-loaded nanocarriers enhance the bioavailability, cellular uptake, and antitumor activity of curcumin. The aforementioned effects are comprehensively discussed in the current review to further direct studies for applying curcumin in lung cancer therapy.

Versatile role of curcumin and its derivatives in lung cancer therapy

The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.

/pdf/akt-inhibitors-new-weapons-in-the-fight-against-breast-4pinb9hfto.pdf

AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

Cell culture is an important and necessary process in drug discovery, cancer research, as well as stem cell study. Most cells are currently cultured using two-dimensional (2D) methods but new and improved methods that implement three-dimensional (3D) cell culturing techniques suggest compelling evidence that much more advanced experiments can be performed yielding valuable insights. When performing 3D cell culture experiments, the cell environment can be manipulated to mimic that of a cell in vivo and provide more accurate data about cell-to-cell interactions, tumor characteristics, drug discovery, metabolic profiling, stem cell research, and other types of diseases. Scaffold based techniques such as hydrogel-based support, polymeric hard material-based support, hydrophilic glass fiber, and organoids are employed, and each provide their own advantages and applications. Likewise, there are also scaffold free techniques used such as hanging drop microplates, magnetic levitation, and spheroid microplates with ultra-low attachment coating. 3D cell culture has the potential to provide alternative ways to study organ behavior via the use of organoids and is expected to eventually bridge the gap between 2D cell culture and animal models. The present review compares 2D cell culture to 3D cell culture, provides the details surrounding the different 3D culture techniques, as well as focuses on the present and future applications of 3D cell culture.

/pdf/is-it-time-to-start-transitioning-from-2d-to-3d-cell-culture-39vwbsi3yl.pdf

Is It Time to Start Transitioning From 2D to 3D Cell Culture

Background: Development of radioresistance in oral squamous cell carcinoma (OSCC) remains a significant problem in cancer treatment, contributing to the lack of improvement in survival trends in recent decades. Effective strategies to overcome radioresistance are necessary to improve the therapeutic outcomes of radiotherapy in OSCC patients. Methods: Cells and xenograft tumors were irradiated using the Small Animal Radiation Research Platform. AKT inhibitor capivasertib (AZD5363) was encapsulated into cathepsin B-responsible nanoparticles (NPs) for tumor-specific delivery. Cell viability was measured by alamarBlue, cell growth was determined by colony formation and 3D culture, and apoptosis was assessed by flow cytometry with the staining of Fluorescein isothiocyanate (FITC) Annexin V and PI. An orthotopic tongue tumor model was used to evaluate the in vivo therapeutic effects. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. Results: We show that upregulation of AKT signaling is the critical mechanism for radioresistance in OSCC cells, and AKT inactivation by a selective and potent AKT inhibitor capivasertib results in radiosensitivity. Moreover, relative to irradiation (IR) alone, IR combined with the delivery of capivasertib in association with tumor-seeking NPs greatly enhanced tumor cell repression in 3D cell cultures and OSCC tumor shrinkage in an orthotopic mouse model. Conclusions: These data indicate that capivasertib is a potent agent that sensitizes radioresistant OSCC cells to IR and is a promising strategy to overcome failure of radiotherapy in OSCC patients.

Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib

In vitro cancer research models require the utmost accuracy and precision to effectively investigate physiological pathways and mechanisms, as well as test the therapeutic efficacy of anticancer drugs. Although two-dimensional (2D) cell culture models have been the traditional hallmark of cancer research, increasing evidence suggests 2D tumor models cannot accurately recapitulate complex aspects of tumor cells and drug responses. Three-dimensional (3D) cell cultures, however, are more physiologically relevant in oncology as they model the cancer network and microenvironment better, allowing for development and assessment of natural products and other anticancer drugs. The present review outlines unprecedented ways in which multicellular spheroid models, organoid models, hydrogel models, microfluidic devices, microfiber scaffold models, and tissue-engineered scaffold models are used in this research. The future of cancer research lies within 3D cell cultures, and as this approach improves, cancer research will continue to advance.

The New Frontier of Three-Dimensional Culture Models to Scale-Up Cancer Research.

There is no consensus about the effective dosages of melatonin in cancer management, thus, it is imperative to fully understand the dose-dependent responsiveness of cancer cells to melatonin and the underlying mechanisms. Head and neck squamous cell carcinoma (HNSCC) cells with or without melatonin treatment were used as a research platform. Gene depletion was achieved by short hairpin RNA, small interfering RNA, and CRISPR/Cas9. Molecular changes and regulations were assessed by Western blotting, quantitative RT-PCR (qRT-PCR), immunohistochemistry, and chromatin Immunoprecipitation coupled with qPCR (ChIP-qPCR). The therapeutic efficacy of FGF19/FGFR4 inhibition in melatonin-mediated tumor growth and metastasis was evaluated in orthotopic tongue tumor mice. The effect of melatonin on controlling cell motility and metastasis varies in HNSCC cells, which is dose-dependent. Mechanistically, high-dose melatonin facilitates the upregulation of FGF19 expression through activating endoplasmic stress (ER)-associated protein kinase RNA-like endoplasmic reticulum kinase (PERK)-Eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor 4 (ATF4) pathway, which in turn promotes FGFR4-Vimentin invasive signaling and attenuates the role of melatonin in repressing metastasis. Intriguingly, following long-term exposure to high-dose melatonin, epithelial HNSCC cells revert the process towards mesenchymal transition and turn more aggressive, which is enabled by FGF19/FGFR4 upregulation and alleviated by genetic depletion of the FGF19 and FGFR4 genes or the treatment of FGFR4 inhibitor H3B-6527. Our study gains novel mechanistic insights into melatonin-mediated modulation of FGF19/FGFR4 signaling in HNSCC, demonstrating that activating this molecular node confines the role of melatonin in suppressing metastasis and even triggers the switch of its function from anti-metastasis to metastasis promotion. The blockade of FGF19/FGFR4 signaling would have great potential in improving the efficacy of melatonin supplements in cancer treatment.

/pdf/fgf19-fgfr4-signaling-axis-confines-and-switches-the-role-of-2fa9az218d.pdf

Caleb Jensen

Papers

Is It Time to Start Transitioning From 2D to 3D Cell Culture

Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib

The New Frontier of Three-Dimensional Culture Models to Scale-Up Cancer Research.

FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis