Patient-derived tumor xenografts (PDXs), in which tumor fragments surgically dissected from cancer patients are directly transplanted into immunodeficient mice, have emerged as a useful model for ...translational research aimed at facilitating precision medicine. PDX susceptibility to anti-cancer drugs is closely correlated with clinical data in patients, from whom PDX models have been derived. Accumulating evidence suggests that PDX models are highly effective in predicting the efficacy of both conventional and novel anti-cancer therapeutics. This also allows "co-clinical trials," in which pre-clinical investigations in vivo and clinical trials could be performed in parallel or sequentially to assess drug efficacy in patients and PDXs. However, tumor heterogeneity present in PDX models and in the original tumor samples constitutes an obstacle for application of PDX models. Moreover, human stromal cells originally present in tumors dissected from patients are gradually replaced by host stromal cells as the xenograft grows. This replacement by murine stroma could preclude analysis of human tumor-stroma interactions, as some mouse stromal cytokines might not affect human carcinoma cells in PDX models. The present review highlights the biological and clinical significance of PDX models and three-dimensional patient-derived tumor organoid cultures of several kinds of solid tumors, such as those of the colon, pancreas, brain, breast, lung, skin, and ovary.
Accumulating evidence indicates that intratumoral heterogeneity contributes to the development of resistance to anticancer therapeutics. Fibroblasts, which are components of the paraneoplastic ...stroma, play a crucial role in the wound-healing process. Activated fibroblasts accumulate in the wound and are involved in many aspects of the tissue remodeling cascade that initiates the repair process and prevents further tissue damage. The pathophysiological roles of cancer-associated fibroblasts (CAFs) in the heterogeneous tumor microenvironment have attracted increasing interest. CAFs play crucial roles in tumor progression and the response to chemotherapy. Several cytokines and chemokines are involved in the conversion of normal fibroblasts into CAFs, and some of these form a feedback loop between cancer cells and CAFs. In addition, the physical force between tumor cells and CAFs promotes cooperative invasion or co-migration of both types of cells. Pro-inflammatory cytokines, such as leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), are secreted by both cancer cells and CAFs, and mediate the epigenetic modification of CAFs. This enhances the pro-tumorigenic function of CAFs mediated by promoting actomyosin contractility and extracellular matrix remodeling to form the tracks used for collective cancer cell migration. The concept of intra-tumoral CAF heterogeneity refers to the presence of inflammatory CAFs with low levels of α-smooth muscle actin (α-SMA) and high levels of IL-6 expression, which are in striking contrast to transforming growth factor-β (TGF-β)-dependent myofibroblastic CAFs with high α-SMA expression levels. CAF populations that suppress tumor growth and progression through stroma-specific Hedgehog (Hh) activation have been detected in different murine tumor models including those of the bladder, colon, and pancreas. A new therapeutic strategy targeting CAFs is the "stromal switch," in which tumor-promoting CAFs are changed into tumor-retarding CAFs with attenuated stromal stiffness. Several molecular mechanisms that can be exploited to design personalized anticancer therapies targeting CAFs remain to be elucidated. Strategies aimed at targeting the tumor stroma as well as tumor cells themselves have attracted academic attention for their application in precision medicine. This novel review discusses the role of the activation of EGFR, Wnt/β-catenin, Hippo, TGF-β, and JAK/STAT cascades in CAFs in relation to the chemoresistance and invasive/metastatic behavior of cancer cells. For instance, although activated EGFR signaling contributes to collective cell migration in cooperation with CAFs, an activated Hippo pathway is responsible for stromal stiffness resulting in the collapse of neoplastic blood vessels. Therefore, identifying the signaling pathways that are activated under specific conditions is crucial for precision medicine.
Tumor tissue is composed of cancer cells and surrounding stromal cells with diverse genetic/epigenetic backgrounds, a situation known as intra-tumoral heterogeneity. Cancer cells are surrounded by a ...totally different microenvironment than that of normal cells; consequently, tumor cells must exhibit rapidly adaptive responses to hypoxia and hypo-nutrient conditions. This phenomenon of changes of tumor cellular bioenergetics, called "metabolic reprogramming", has been recognized as one of 10 hallmarks of cancer. Metabolic reprogramming is required for both malignant transformation and tumor development, including invasion and metastasis. Although the Warburg effect has been widely accepted as a common feature of metabolic reprogramming, accumulating evidence has revealed that tumor cells depend on mitochondrial metabolism as well as aerobic glycolysis. Remarkably, cancer-associated fibroblasts in tumor stroma tend to activate both glycolysis and autophagy in contrast to neighboring cancer cells, which leads to a reverse Warburg effect. Heterogeneity of monocarboxylate transporter expression reflects cellular metabolic heterogeneity with respect to the production and uptake of lactate. In tumor tissue, metabolic heterogeneity induces metabolic symbiosis, which is responsible for adaptation to drastic changes in the nutrient microenvironment resulting from chemotherapy. In addition, metabolic heterogeneity is responsible for the failure to induce the same therapeutic effect against cancer cells as a whole. In particular, cancer stem cells exhibit several biological features responsible for resistance to conventional anti-tumor therapies. Consequently, cancer stem cells tend to form minimal residual disease after chemotherapy and exhibit metastatic potential with additional metabolic reprogramming. This type of altered metabolic reprogramming leads to adaptive/acquired resistance to anti-tumor therapy. Collectively, complex and dynamic metabolic reprogramming should be regarded as a reflection of the "robustness" of tumor cells against unfavorable conditions. This review focuses on the concept of metabolic reprogramming in heterogeneous tumor tissue, and further emphasizes the importance of developing novel therapeutic strategies based on drug repositioning.
The pathophysiological roles and the therapeutic potentials of Myc family are reviewed in this article. The physiological functions and molecular machineries in stem cells, including embryonic stem ...(ES) cells and induced pluripotent stem (iPS) cells, are clearly described. The c-Myc/Max complex inhibits the ectopic differentiation of both types of artificial stem cells. Whereas c-Myc plays a fundamental role as a "double-edged sword" promoting both iPS cells generation and malignant transformation, L-Myc contributes to the nuclear reprogramming with the significant down-regulation of differentiation-associated genetic expression. Furthermore, given the therapeutic resistance of neuroendocrine tumors such as small-cell lung cancer and neuroblastoma, the roles of N-Myc in difficult-to-treat tumors are discussed. N-Myc and p53 exhibit the co-localization in the nucleus and alter p53-dependent transcriptional responses which are necessary for DNA repair, anti-apoptosis, and lipid metabolic reprogramming. NCYM protein stabilizes N-Myc, resulting in the stimulation of Oct4 expression, while Oct4 induces both N-Myc and NCYM via direct transcriptional activation of N-Myc, corrected thereby leading to the enhanced metastatic potential. Importantly enough, accumulating evidence strongly suggests that c-Myc can be a promising therapeutic target molecule among Myc family in terms of the biological characteristics of cancer stem-like cells (CSCs). The presence of CSCs leads to the intra-tumoral heterogeneity, which is mainly responsible for the therapeutic resistance. Mechanistically, it has been shown that Myc-induced epigenetic reprogramming enhances the CSC phenotypes. In this review article, the author describes two major therapeutic strategies of CSCs by targeting c-Myc; Firstly, Myc-dependent metabolic reprogramming is closely related to CD44 variant-dependent redox stress regulation in CSCs. It has been shown that c-Myc increases NADPH production via enhanced glutaminolysis with a finely-regulated mechanism. Secondly, the dormancy of CSCs due to FBW7-depedent c-Myc degradation pathway is also responsible for the therapeutic resistance to the conventional anti-tumor agents, the action points of which are largely dependent on the operation of the cell cycle. That is why the loss-of-functional mutations of FBW7 gene are expected to trigger "awakening" of dormant CSCs in the niche with c-Myc up-regulation. Collectively, although the further research is warranted to develop the effective anti-tumor therapeutic strategy targeting Myc family, we cancer researchers should always catch up with the current advances in the complex functions of Myc family in highly-malignant and heterogeneous tumor cells to realize the precision medicine.
The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents ...and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy-lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a "double-edged sword" for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that "conventional" agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing attention because the safety profiles of these medicines are well known. Antimalarial agents such as artemisinin and disease-modifying antirheumatic drug (DMARD) are the typical examples of drug re-positioning which affect the autophagy regulation for the therapeutic use. This review article focuses on recent advances in some of the novel therapeutic strategies that target autophagy with a view to treating/preventing malignant neoplasms.
Cancer stem cells (CSCs) are undifferentiated cancer cells with a high tumorigenic activity, the ability to undergo self‐renewal, and a multilineage differentiation potential. Cancer stem cells are ...responsible for the development of tumor cell heterogeneity, a key feature for resistance to anticancer treatments including conventional chemotherapy, radiation therapy, and molecularly targeted therapy. Furthermore, minimal residual disease, the major cause of cancer recurrence and metastasis, is enriched in CSCs. Cancer stem cells also possess the property of “robustness”, which encompasses several characteristics including a slow cell cycle, the ability to detoxify or mediate the efflux of cytotoxic agents, resistance to oxidative stress, and a rapid response to DNA damage, all of which contribute to the development of therapeutic resistance. The identification of mechanisms underlying such characteristics and the development of novel approaches to target them will be required for the therapeutic elimination of CSCs and the complete eradication of tumors. In this review, we focus on two prospective therapeutic approaches that target CSCs with the aim of disrupting their quiescence or redox defense capability.
Cancer stem cells possess the property of “robustness” which leads to the development of therapeutic resistance. The identification of mechanisms underlying such characteristics is required for the therapeutic elimination of CSCs and the complete eradication of tumors.
Cancer cells generate large amounts of lactate derived from glucose regardless of the available oxygen level. Cancer cells finely control ATP synthesis by modulating the uptake of substrates and the ...activity of enzymes involved in aerobic glycolysis (Warburg effect), which enables them to adapt to the tumor microenvironment. However, increasing evidence suggests that mitochondrial metabolism, including the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and glutaminolysis, is paradoxically activated in MYCN-amplified malignancies. Unlike non-amplified cells, MYCN-amplified cancer cells significantly promote OXPHOS-dependent ATP synthesis. Furthermore, tumor cells are differentially dependent on fatty acid β-oxidation (FAO) according to N-Myc status. Therefore, upregulation of FAO-associated enzymes is positively correlated with both N-Myc expression level and poor clinical outcome. This review explores therapeutic strategies targeting cancer stem-like cells for the treatment of tumors associated with MYCN amplification.
Neoplastic epithelial cells coexist in carcinomas with various non-neoplastic stromal cells, together creating the tumor microenvironment. There is a growing interest in the cross-talk between tumor ...cells and stromal fibroblasts referred to as carcinoma-associated fibroblasts (CAFs), which are frequently present in human carcinomas. CAF populations extracted from different human carcinomas have been shown to possess the ability to influence the hallmarks of cancer. Indeed, several mechanisms underlying CAF-promoted tumorigenesis are elucidated. Activated fibroblasts in CAFs are characterized as alpha-smooth muscle actin-positive myofibroblasts and actin-negative fibroblasts, both of which are competent to support tumor growth and progression. There are, however, heterogeneous CAF populations presumably due to the diverse sources of their progenitors in the tumor-associated stroma. Thus, molecular markers allowing identification of bona fide CAF populations with tumor-promoting traits remain under investigation. CAFs and myofibroblasts in wound healing and fibrosis share biological properties and support epithelial cell growth, not only by remodeling the extracellular matrix, but also by producing numerous growth factors and inflammatory cytokines. Notably, accumulating evidence strongly suggests that anti-fibrosis agents suppress tumor development and progression. In this review, we highlight important tumor-promoting roles of CAFs based on their analogies with wound-derived myofibroblasts and discuss the potential therapeutic strategy targeting CAFs.
Superconducting coils can generate high magnetic fields and are used in many applications in medicine, industry and research. A superconducting coil stores enormous amounts of magnetic energy, often ...more than 1 MJ, and this energy is released when a quench occurs. Therefore, quench protection methods, which prevent energy localization, have been developed to protect the coil and peripheral mechanisms. However, shortening the inactive time of the coil must be considered. Even in undamaged coils, in cryogen-free magnets, the coil temperature rises owing to the energy released and requires more time to cool to the operable temperature. Quenching can occur during power outages, training processes, and safety tests in coil manufacturing. Longer recovery times require longer lead times in the coil manufacturing process and result in longer downtime in situ. Therefore, we consider a quench protection method that removes energy from the coil to shorten the recovery time and increases the availability. In this study, we report the results of our study on inductive energy extraction.
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