scholarly journals Interrupting Neuron—Tumor Interactions to Overcome Treatment Resistance

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3741
Author(s):  
Patrick J. Hunt ◽  
Katherine E. Kabotyanski ◽  
George A. Calin ◽  
Tongxin Xie ◽  
Jeffrey N. Myers ◽  
...  
Keyword(s):  
Growth Factors ◽  
Tumor Microenvironment ◽  
Signaling Pathways ◽  
Treatment Strategies ◽  
Treatment Resistance ◽  
Trophic Relationships ◽  
Surgical Interventions ◽  
In Vivo Experiments

Neurons in the tumor microenvironment release neurotransmitters, neuroligins, chemokines, soluble growth factors, and membrane-bound growth factors that solid tumors leverage to drive their own survival and spread. Tumors express nerve-specific growth factors and microRNAs that support local neurons and guide neuronal growth into tumors. The development of feed-forward relationships between tumors and neurons allows tumors to use the perineural space as a sanctuary from therapy. Tumor denervation slows tumor growth in animal models, demonstrating the innervation dependence of growing tumors. Further in vitro and in vivo experiments have identified many of the secreted signaling molecules (e.g., acetylcholine, nerve growth factor) that are passed between neurons and cancer cells, as well as the major signaling pathways (e.g., MAPK/EGFR) involved in these trophic interactions. The molecules involved in these signaling pathways serve as potential biomarkers of disease. Additionally, new treatment strategies focus on using small molecules, receptor agonists, nerve-specific toxins, and surgical interventions to target tumors, neurons, and immune cells of the tumor microenvironment, thereby severing the interactions between tumors and surrounding neurons. This article discusses the mechanisms underlying the trophic relationships formed between neurons and tumors and explores the emerging therapies stemming from this work.

scholarly journals Anti-Cancer Properties of Theaflavins

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 987
Author(s):  
Eric J. O’Neill ◽  
Deborah Termini ◽  
Alexandria Albano ◽  
Evangelia Tsiani
Keyword(s):  
Signaling Pathways ◽  
Cancer Progression ◽  
Treatment Strategies ◽  
B Cell Lymphoma ◽  
Black Tea ◽  
Phosphorylated Akt ◽  
Phenolic Components ◽  
Anti Cancer

Cancer is a disease characterized by aberrant proliferative and apoptotic signaling pathways, leading to uncontrolled proliferation of cancer cells combined with enhanced survival and evasion of cell death. Current treatment strategies are sometimes ineffective in eradicating more aggressive, metastatic forms of cancer, indicating the need to develop novel therapeutics targeting signaling pathways which are essential for cancer progression. Historically, plant-derived compounds have been utilized in the production of pharmaceuticals and chemotherapeutic compounds for the treatment of cancer, including paclitaxel and docetaxel. Theaflavins, phenolic components present in black tea, have demonstrated anti-cancer potential in cell cultures in vitro and in animal studies in vivo. Theaflavins have been shown to inhibit proliferation, survival, and migration of many cancer cellswhile promoting apoptosis. Treatment with theaflavins has been associated with increased levels of cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspases-3, -7, -8, and -9, all markers of apoptosis, and increased expression of the proapoptotic marker Bcl-2-associated X protein (Bax) and concomitant reduction in the antiapoptotic marker B-cell lymphoma 2 (Bcl-2). Additionally, theaflavin treatment reduced phosphorylated Akt, phosphorylated mechanistic target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K), and c-Myc levels with increased expression of the tumour suppressor p53. This review summarizes the current in vitro and in vivo evidence available investigating the anti-cancer effects of theaflavins across various cancer cell lines and animal models.

scholarly journals TGF-β promotes microtube formation in glioblastoma through Thrombospondin 1

2021 ◽  
Author(s):  
Justin V. Joseph ◽  
Capucine R. Magaut ◽  
Simon Storevik ◽  
Luiz H. Geraldo ◽  
Thomas Mathivet ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Network Formation ◽  
Cell Communication ◽  
Treatment Resistance ◽  
Communication Structures ◽  
Oligodendroglial Tumors ◽  
Thrombospondin 1 ◽  
Stem Cell Lines

AbstractMicrotubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular glioblastomas (GBMs), while they are uncommon in chemosensitive IDH-mutant and 1p/19q co-deleted oligodendrogliomas. To identify potential signaling pathways involved in MT formation we performed a bioinformatics analysis of TCGA data showing that the TGF-β pathway is highly activated in GBMs compared to oligodendroglial tumors. In particular we observed that signaling pathways involved in extracellular matrix organization are differentially expressed between these tumor entities. Using patient-derived GBM stem cell lines, we demonstrated that TGF-β1 stimulation promotes enhanced MT formation and communication via Calcium signaling. Inhibition of the TGF-β pathway significantly reduced MT formation and its associated invasion in vitro and in vivo. Downstream of TGF-β, we identified thrombospondin 1 (TSP1) as a potential mediator of MT formation in GBM through SMAD activation. TSP1 was upregulated upon TGF-β stimulation and enhanced MT formation, which was inhibited by TSP1 shRNAs in vitro and in vivo. In conclusion, TGF-β and its downstream mediator TSP1 are important mediators of the MT network in GBM and blocking this pathway could potentially help to break the complex MT driven invasion/ resistance network.

scholarly journals An In Vitro and In Vivo Comparison of Osteogenic Differentiation of Human Mesenchymal Stromal/Stem Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-23
Author(s):  
Jamie Mollentze ◽  
Chrisna Durandt ◽  
Michael S. Pepper
Keyword(s):  
Stem Cells ◽  
Osteogenic Differentiation ◽  
Treatment Strategies ◽  
Bone Disorders ◽  
In Vivo Experiments ◽  
Confounding Variables ◽  
Living Organisms ◽  
Stromal Stem Cells

The use of stem cells in regenerative medicine, including tissue engineering and transplantation, has generated a great deal of enthusiasm. Mesenchymal stromal/stem cells (MSCs) can be isolated from various tissues, most commonly, bone marrow but more recently adipose tissue, dental pulp, and Wharton’s jelly, to name a few. MSCs display varying phenotypic profiles and osteogenic differentiating capacity depending and their site of origin. MSCs have been successfully differentiated into osteoblasts both in vitro an in vivo but discrepancies exist when the two are compared: what happens in vitro does not necessarily happen in vivo, and it is therefore important to understand why these differences occur. The osteogenic process is a complex network of transcription factors, stimulators, inhibitors, proteins, etc., and in vivo experiments are helpful in evaluating the various aspects of this osteogenic process without distractions and confounding variables. With that in mind, the results of in vitro experiments need to be carefully considered and interpreted with caution as they do not perfectly replicate the conditions found within living organisms. This is where in vivo experiments help us better understand interactions that might occur in the osteogenic process that cannot be replicated in vitro. Potentially, these differences could also be exploited to develop an optimal MSC cell therapeutic product that can be used for bone disorders. There are many bone disorders, most of which cause a great deal of discomfort. Clinically acceptable protocols could be developed in which MSCs are used to aid in bone regeneration providing relief for patients with chronic pain. The aim of this review is to examine the differences between studies conducted in vitro and in vivo with regard to the osteogenic process to better define the gaps in current osteogenic research. By better understanding osteogenic differentiation, we can better define treatment strategies for various bone disorders.

scholarly journals Astrocytes donate mitochondria to increase glioblastoma tumorigenicity

2021 ◽  
Author(s):  
Justin Lathia ◽  
Dionysios Watson ◽  
Defne Bayik ◽  
Sarah Williford ◽  
Adam Lauko ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cell Communication ◽  
Treatment Resistance ◽  
Extracellular Vesicle ◽  
Host Cells ◽  
Molecular Events ◽  
Mitochondrial Transfer ◽  
New Research

Abstract Glioblastoma (GBM), the most common primary brain cancer in adults1, is characterized by numerous cell-intrinsic/extrinsic interactions that drive tumorigenesis. In addition to cell-surface and secreted protein/extracellular vesicle interactions2,3, treatment resistance of GBM is augmented by the formation of cytoplasmic interconnections and junctions among tumor cells4. These cytoplasmic bridges among tumor cells enable exchange of cellular metabolites as well as mitochondria4, which can play a key role in metabolic function and cellular programming in GBM5,6. However, the contribution of the tumor microenvironment to mitochondrial transfer, as well as the downstream impact of mitochondrial transfer on GBM remains poorly characterized. Here we identified horizontal mitochondrial transfer from the tumor microenvironment as a mechanism that enhances tumorigenesis in glioblastoma. We found that this transfer occurs primarily from brain-resident cells, including astrocytes, and can be appreciated in vitro and in vivo through intercellular connections between GBM cells and non-malignant host cells. The acquisition of astrocyte mitochondria drives an overall enhancement of mitochondrial membrane potential and metabolic capacity, while increasing glioblastoma cell self-renewal and tumor-initiating capacity. Collectively, our findings demonstrate that astrocyte mitochondrial transfer augments the tumorigenic capacity of glioblastoma cells and reveals a previously unknown cell-cell communication mechanism that drives tumor growth. We anticipate our findings will open new research directions to decipher the molecular events linking mitochondria acquisition from non-malignant cells to increased tumorigenicity of recipient GBM cells. This line of research will lead to new therapeutic opportunities targeting this understudied phenomenon and its sequelae in GBM.

scholarly journals Measuring Tumor Microenvironment pH During Radiotherapy Using a Novel Cerenkov Emission Multispectral Optical Probe Based on Silicon Photomultipliers

2021 ◽  
Vol 9 ◽  
Author(s):  
Ibrahim Oraiqat ◽  
Essam Al-Snayyan ◽  
Andrew Calcaterra ◽  
Roy Clarke ◽  
Alnawaz Rehemtulla ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
External Beam Radiotherapy ◽  
Treatment Resistance ◽  
Optical Probe ◽  
Silicon Photomultiplier ◽  
Treatment Pathways ◽  
Tumor Ph ◽  
Cerenkov Emission

Cerenkov Emission (CE) multispectral analysis with silicon photomultiplier (SiPM)-based optical probes is a promising tool for online tumor microenvironment interrogation and targeting during radiotherapy delivery. With the extreme sensitivity of SiPMs, deep tissue multispectral CE measurements can be realized in a clinical setting. In this work, we utilize our Cerenkov Emission Multi-spectral Imaging (CMSI) prototype probe to interrogate the spectral components of the CE signal generated during external beam radiotherapy. Our results demonstrated that CMSI enables effective probing of in vitro quantitative changes in the pH of cell media to monitor cancer cell proliferation after various treatment pathways and differentiate between varying treatment resistance cell lines. In addition, the feasibility of using the CMSI probe in vivo was also successfully demonstrated by measuring tumor pH during a pilot mouse study.

scholarly journals Src acts as the target of matrine to inhibit the proliferation of cancer cells by regulating phosphorylation signaling pathways

2020 ◽  
Author(s):  
Xi Zhang ◽  
Hui Xu ◽  
Xiaoyang Bi ◽  
Guoqing Hou ◽  
Andong Liu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Kinase Activity ◽  
Src Kinase ◽  
Kinase Domain ◽  
Akt Phosphorylation ◽  
In Vivo Experiments

Background and Purpose: Identification of accurate targets is essential for a successful development of targeted therapy in cancer. Studies have shown that matrine has antitumor activity against many types of cancers. However, the direct target in cancer cells of its anticancer effect has not been identified. The purpose of this study was to find the molecular target of matrine to inhibit the proliferation of cancer cells and explore its mechanism of action. Experimental Approach: The effect of matrine on the proliferation of cancer cells were examined by MTT assay. Pull-down assay and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) were performed to explore the target of matrine. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which matrine targeted Src to regulate the downstream signaling pathways of Src in cancer cells. Key Results: Herein we showed that matrine inhibited the proliferation of cancer in vitro and in vivo. Pull-down assay with matrine-amino coupling resins (MA beads) and LC-MS/MS identified Src as the target of matrine. Src kinase domain is required for its interaction with matrine and Ala392 in the kinase domain participated in matrine-Src interaction. Intriguingly, matrine was proven to inhibit Src kinase activity in a non-ATP-competitive manner by blocking the autophosphorylation of Tyr419. Matrine down-regulated the phosphorylation levels of MAPK/ERK, JAK2/STAT3 and PI3K/Akt signaling pathways. Conclusions and Implications: Collectively, matrine targeted Src, inhibited kinase activity and down-regulated its downstream MAPK/ERK, JAK2/STAT3 and PI3K/Akt phosphorylation signaling pathways to inhibit the proliferation of cancer cells.

scholarly journals Matrine inhibits the development and progression of ovarian cancer by repressing cancer associated phosphorylation signaling pathways

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Xi Zhang ◽  
Guoqing Hou ◽  
Andong Liu ◽  
Hui Xu ◽  
Yang Guan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Side Effects ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Chemotherapy Resistance ◽  
Treatment Strategies ◽  
Ovarian Cancer Cells

Abstract Ovarian cancer remains the most lethal gynecologic malignancy with late detection and acquired chemoresistance. Advanced understanding of the pathophysiology and novel treatment strategies are urgently required. A growing body of proteomic investigations suggest that phosphorylation has a pivotal role in the regulation of ovarian cancer associated signaling pathways. Matrine has been extensively studied for its potent anti-tumor activities. However, its effect on ovarian cancer cells and underlying molecular mechanisms remain unclear. Herein we showed that matrine treatment inhibited the development and progression of ovarian cancer cells by regulating proliferation, apoptosis, autophagy, invasion and angiogenesis. Matrine treatment retarded the cancer associated signaling transduction by decreasing the phosphorylation levels of ERK1/2, MEK1/2, PI3K, Akt, mTOR, FAK, RhoA, VEGFR2, and Tie2 in vitro and in vivo. Moreover, matrine showed excellent antitumor effect on chemoresistant ovarian cancer cells. No obvious toxic side effects were observed in matrine-administrated mice. As the natural agent, matrine has the potential to be the targeting drug against ovarian cancer cells with the advantages of overcoming the chemotherapy resistance and decreasing the toxic side effects.

Grade-targeted nanoparticles for improved hypoxic tumor microenvironment and enhanced photodynamic cancer therapy

Nanomedicine ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. 221-235 ◽  
Author(s):  
Ying-kai Tao ◽  
Xiao-yang Hou ◽  
Huan Gao ◽  
Xin Zhang ◽  
Feng-mei Zuo ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Tumor Microenvironment ◽  
Aminolevulinic Acid ◽  
Double Emulsion ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
In Vivo Experiments ◽  
Limited Diffusion

Background: The hypoxia of the tumor microenvironment (TME), low transfer efficiency of photosensitizers and limited diffusion distance of reactive oxygen species restrict the application of photodynamic therapy (PDT). Aim: To produce TME-responsive and effective nanoparticles for sensitizing PDT. Materials & methods: CD44 and mitochondria grade-targeted hyaluronic acid (HA)-triphenylphosphine (TPP)-aminolevulinic acid (ALA)-catalase (CAT) nanoparticles (HTACNPs) were synthesized via a modified double-emulsion method. In vitro and in vivo experiments were performed to investigate the antitumor efficacy of HTACNP-mediated PDT. Results: HTACNPs specifically targeted MV3 cells and the mitochondria and produced O2 to relieve TME hypoxia. HTACNP-mediated PDT produced reactive oxygen species to induce irreversible cell apoptosis. HTACNP-PDT inhibited melanoma growth effectively in vivo. Conclusion: HTACNP-mediated PDT improved TME hypoxia and effectively enhanced PDT for cancer.

scholarly journals The Effects of Resveratrol on Prostate Cancer through Targeting the Tumor Microenvironment

2021 ◽  
Vol 11 (1) ◽  
pp. 16-32
Author(s):  
Natalie Silk ◽  
Jeremy Reich ◽  
Rahul Sinha ◽  
Shivansh Chawla ◽  
Kyla Geary ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
Cancer Prevention ◽  
Molecular Mechanisms ◽  
The United States ◽  
In Vivo Experiments ◽  
Cancer Initiation ◽  
Proliferation And Metastasis

Prostate cancer is one of the most common cancers diagnosed in men in the United States and the second leading cause of cancer-related deaths worldwide. Since over 60% of prostate cancer cases occur in men over 65 years of age, and this population will increase steadily in the coming years, prostate cancer will be a major cancer-related burden in the foreseeable future. Accumulating data from more recent research suggest that the tumor microenvironment (TME) plays a previously unrecognized role in every stage of cancer development, including initiation, proliferation, and metastasis. Prostate cancer is not only diagnosed in the late stages of life, but also progresses relatively slowly. This makes prostate cancer an ideal model system for exploring the potential of natural products as cancer prevention and/or treatment reagents because they usually act relatively slowly compared to most synthetic drugs. Resveratrol (RSV) is a naturally occurring stilbenoid and possesses strong anti-cancer properties with few adverse effects. Accumulating data from both in vitro and in vivo experiments indicate that RSV can interfere with prostate cancer initiation and progression by targeting the TME. Therefore, this review is aimed to summarize the recent advancement in RSV-inhibited prostate cancer initiation, proliferation, and metastasis as well as the underlying molecular mechanisms, with particular emphasis on the effect of RSV on TME. This will not only better our understanding of prostate cancer TMEs, but also pave the way for the development of RSV as a potential reagent for prostate cancer prevention and/or therapy.

Cancer treatments using low-temperature plasma

2021 ◽  
Vol 28 ◽  
Author(s):  
Hiromasa Tanaka ◽  
Masaaki Mizuno ◽  
Kenji Ishikawa ◽  
Shinya Toyokuni ◽  
Hiroaki Kajiyama ◽  
...  
Keyword(s):  
Low Temperature ◽  
Signaling Pathways ◽  
Medical Application ◽  
Low Temperature Plasma ◽  
Key Factors ◽  
Temperature Plasma ◽  
In Vivo Experiments ◽  
Stress Dependent

: Low-temperature plasma (LTP) is a partially ionized gas that contains electrons, ions, radicals, light, etc. Recently, the bio-medical application of LTP has become a hot topic in plasma science and biological science. Cancer treatment with plasma is the most challenging topic in plasma bio-medical applications. Many in vitro and in vivo experiments have been conducted to investigate the anti-tumor effects of LTP. Extracellular reactive oxygen and nitrogen species (RONS) in plasma-activated solutions are key factors for the anti-tumor effects, and amino acid modifications by LTP may affect cellular responses. Intracellular RONS are also key factors for the anti-tumor effects. Various signaling pathways such as p53 signaling pathways, survival and proliferation signaling pathways, and oxidative stress-dependent signaling pathways are activated by LTP.

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