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Cancers of the breast, prostate and intestinal tract account for most cancer-associated deaths in humans and represent several of the highest incidence human neoplasms. Therefore, understanding the underlying pathophysiology, including the formation and propagation of these cancers, is key to designing potential treatments. Over the last 50 years or more, genetically engineered mouse models (GEMMs) have been instrumental platforms to our discovery of neoplastic disease as many follow near-identical molecular and histological progression as human tumours. In this mini review, we summarize three key preclinical models and focus on some of the major findings in relation to clinical care. We discuss the MMTV-PyMT (polyomavirus middle T antigen) mouse, TRAMP (transgenic adenocarcinoma mouse prostate) mouse and APCMin (multiple intestinal neoplasm mutation of APC gene) mouse, which mimic breast, prostate and intestinal cancers, respectively. We aim to describe the significant contributions these GEMMs have made to our collective understanding of high-incidence cancers as well as briefly discuss the limitations of each model as a device for therapeutic discovery. [ABSTRACT FROM AUTHOR]

• Impulsive differential equations are used to capture the characteristics of intermittent androgen deprivation therapy. • The dynamics of tumours are sensitive to stochastic noise and tumour antigenicity. • The sufficient conditions for the existence of ergodic stationary distribution are established. • The results show that comprehensive therapy is more effective than a single therapy. Intermittent androgen deprivation therapy is one of the most commonly used therapeutic regimens for treating prostate cancer. Immunotherapy with dendritic cells, which act as the most robust antigen-presenting cells, are regarded as an effective method for the treatment of advanced prostate cancer. This paper utilizes impulsive differential equations to describe the combinations of a dendritic cell vaccine and intermittent androgen therapy with white noise. The tumour-free solution is obtained and the unique global positive solution of the system is explored. Then it is proved that the solutions of the system are stochastic ultimately bounded and stochastically permanent. In addition, threshold conditions for the extinction and persistence of prostate cancer cells are derived, and the stationary distribution and ergodicity of the system are investigated. Finally, numerical studies and the biological significance of the results are discussed. [ABSTRACT FROM AUTHOR]

In this paper, we have studied a three-dimensional model to describe the behavior of tumor cells in the absence of the immune response, which is composed of tumor, normal and fat cells (TNF) under time delay effect. The center manifold theory has been used to study the bifurcation behavior. It is proven that TNF model undergoes codimension-1 bifurcation, while Hopf bifurcation does not occur in the non-delay model. For delayed TNF, we take into the late response of fat cells to tumor cells. Consequently, the delay factor is a considerable parameter in TNF model. Hence, we presented a formula of the time delay value for the occurrence of periodic solutions. Additionally, the stability of Hopf bifurcation was analysed. Numerical simulations are provided to illustrate and extend the theoretical results, we provide our study with numerical simulations inclusive families of periodic solutions. [ABSTRACT FROM AUTHOR]

The MAPK/ERK pathway regulates a variety of physiological cellular functions, including cell proliferation and survival. It is abnormally activated in many types of human cancers in response to driver mutations in regulators of this pathway that trigger tumor initiation. The early steps of oncogenic progression downstream of ERK overactivation are poorly understood due to a lack of appropriate models. We show here that ERK1/2 overactivation in the trunk neural tube of the chicken embryo through expression of a constitutively active form of the upstream kinase MEK1 (MEK1ca), rapidly provokes a profound change in the transcriptional signature of developing spinal cord cells. These changes are concordant with a previously established role of the tyrosine kinase receptor ligand FGF8 acting via the ERK1/2 effectors to maintain an undifferentiated state. Furthermore, we show that MEK1ca-transfected spinal cord cells lose neuronal identity, retain caudal markers, and ectopically express potential effector oncogenes, such as AQP1. MEK1ca expression in the developing spinal cord from the chicken embryo is thus a tractable in vivo model to identify the mechanisms fostering neoplasia and malignancy in ERK-induced tumorigenesis of neural origins. [ABSTRACT FROM AUTHOR]

[Display omitted] Preclinical studies in rodent models have been a pivotal role in human clinical research, but many of them fail in the translational process. Spontaneous tumors in pet dogs have the potential to bridge the gap between preclinical models and human clinical trials. Their natural occurrence in an immunocompetent system overcome the limitations of preclinical rodent models. Due to its reasonable cellular, molecular, and genetic homology to humans, the pet dog represents a valuable model to accelerate the translation of preclinical studies to clinical trials in humans, actually with benefits for both species. Moreover, their unique genetic features of breeding and breed-related mutations have contributed to assess and optimize therapeutics in individuals with different genetic backgrounds. This review aims to outline four main immunotherapy approaches – cancer vaccines, adaptive T-cell transfer, antibodies, and cytokines –, under research in veterinary medicine and how they can serve the clinical application crosstalk with humans. [ABSTRACT FROM AUTHOR]

Abstract Glioblastoma (GBM) is an aggressive malignant brain tumor with median survival of 12 months and 5-year survival rate less than 5%. GBM is highly vascularized, and the interactions between tumor and endothelial cells play an important role in driving tumor growth. To study tumor-endothelial interactions, the gold standard co-culture model is transwell culture, which fails to recapitulate the biochemical or physical cues found in tumor niche. Recently, we reported the development of poly(ethylene-glycol)-based hydrogels as 3D niche that supported GBM proliferation and invasion. To further mimic the microanatomical architecture of tumor-endothelial interactions in vivo, here we developed a hydrogel-based co-culture model that mimics the spatial organization of tumor and endothelial cells. To increase the physiological relevance, patient-derived GBM cells and mouse brain endothelial cells were used as model cell types. Using hydrolytically-degradable alginate fibers as porogens, endothelial cells were deployed and patterned into vessel-like structures in 3D hydrogels with high cell viability and retention of endothelial phenotype. Co-culture led to a significant increase in GBM cell proliferation and decrease in endothelial cell expression of cell adhesion proteins. In summary, we have developed a novel 3D co-culture model that mimics the in vivo spatial organization of brain tumor and endothelial cells. Such model may provide a valuable tool for future mechanistic studies to elucidate the effects of tumor-endothelial interactions on tumor progression in a more physiologically-relevant manner. [ABSTRACT FROM AUTHOR]

Cancer research uses in vitro studies for controllable analysis of tumor behavior and preclinical testing of therapeutics. Shortcomings of basic cell culture systems in recreating in vivo interactions have driven the development of more efficient and biomimetic in vitro environments for cancer research. Assimilation of certain developments in tissue engineering will accelerate and improve the design of these environments. With the continual improvement of the tumor engineering field, the next step is towards macroscopic systems such as scaffold-supported, flow-perfused macroscale tumor bioreactors. Surface modifications of synthetic scaffolds allow for targeted cell adhesion and improved ECM development. Flow perfusion has emerged as means to expose cancerous tissues to critical biomechanical forces for tumor progression while simultaneously improving nutrient and waste transport. Macroscale perfusable systems allow for non-destructive real-time monitoring using biosensors capable of improving understanding of in vitro tumor development at reduced cost and waste. The combination of macroscale perfusable systems, surface-modified synthetic scaffolds, and non-destructive real-time monitoring will provide advanced platforms for in vitro modeling of tumor development, with broad applications in basic tumor research and preclinical drug development. [ABSTRACT FROM AUTHOR]

Most epithelial tissues are maintained by stem cells that produce the different cell lineages required for proper tissue function. Constant communication between different cell types ensures precise regulation of stem cell behavior and cell fate decisions. These cell-cell interactions are often disrupted during tumorigenesis, but mechanisms by which they are co-opted to support tumor growth in different genetic contexts are poorly understood. Here, we introduce PromoterSwitch, a genetic platform we established to generate large, transformed clones derived from individual adult Drosophila intestinal stem/progenitor cells. We show that cancer-driving genetic alterations representing common colon tumor genome landscapes disrupt cell fate decisions within transformed tissue and result in the emergence of abnormal cell fates. We also show that transformed enteroendocrine cells, a differentiated, hormone-secreting cell lineage, support tumor growth by regulating intestinal stem cell proliferation through multiple genotype-dependent mechanisms, which represent potential vulnerabilities that could be exploited for therapy. [Display omitted] • PromoterSwitch (PS) allows more refined genetic manipulations in Drosophila • Cancer-driving genetic alterations disrupt cell fate decisions in the intestine • Transformed enteroendocrine cells (EEs) promote intestinal transformation • The EE hormone Tachykinin supports tumorigenesis through genotype-dependent mechanisms Quintero and Bangi use a genetic tool to show that cancer-driving genetic alterations disrupt cell fate decisions in the adult fly intestine, resulting in tumor-like growths that capture the cell-type heterogeneity of cancer. They also identify a tumor-promoting role for hormone-secreting enteroendocrine cells mediated by multiple genotype-dependent mechanisms. [ABSTRACT FROM AUTHOR]

This paper presents an intelligent controller for MIMO cancer immunotherapy system. The treatment objective is obtaining a suitable scheduling scheme for drug dosage to decrease the tumor cells. Utilizing the back-stepping technique and property of universal approximation of the fuzzy systems, an adaptive fuzzy back-stepping controller for the MIMO cancer immunotherapy system is proposed. The response of closed-loop system is valid for any initial conditions and robust performance of the overall system for a wide range of the parameter uncertainties can be guaranteed. Simulation results clarify the efficiency of the suggested approach in the reduction of the number of tumor cells in the cancer model. [ABSTRACT FROM AUTHOR]

This research proposes a mathematical model of cancer treatment with chemotherapy using a fractal fractional Mittag-Leffler operator with non-integer order. The model is analyzed both qualitatively and quantitatively. The control of cancer treatment with chemotherapy effects is established using a fractal fractional operator with a Mittag-Leffler kernel and control theory. The effect of global derivative, existence of unique solutions, and boundedness of proposed system is verified. Solutions are produced using a two-step Lagrange polynomial, and numerical simulations are carried out to illustrate the theoretical results. Cancer treatment with chemotherapy effects are verified from our justified results and predictions are made by simulation using MATLAB. Controllability and observability of the proposed system is also treated for linear control system to observe the close loop design with chemotherapy as an input and treated cells as the output. • Model of cancer treatment with chemotherapy using a fractal fractional Mittag–Leffler operator. • The model is analyzed both qualitatively and quantitatively. • The effect of global derivative, and boundedness of proposed system is verified. • Solutions are produced using a two-step Lagrange polynomial, and numerical simulations are carried out. • Controllability and observability of the proposed system is treated for linear control system. [ABSTRACT FROM AUTHOR]

Although recent advances in oncology emphasized the role of microenvironment in tumor growth, the role of delays for modeling tumor growth is still uncertain. In this paper, we considered a model, describing the interactions of tumor cells with their microenvironment made of immune cells and host cells, in which we inserted, as suggested by the clinicians, two time delays, one in the interactions between tumor cells and immune cells and, one in the action of immune cells on tumor cells. We showed analytically that the singular point associated with the co-existence of the three cell populations loses its stability via a Hopf bifurcation. We analytically calculated a range of the delays over which tumor cells are inhibited by immune cells and over which a period-1 limit cycle induced by this Hopf bifurcation is observed. By using a global modeling technique, we investigated how the dynamics observed with two delays can be reproduced by a similar model without delays. The effects of these two delays were thus interpreted in terms of interactions between the cell populations. [ABSTRACT FROM AUTHOR]

The construction of tumor model plays a crucial role in preclinical drug evaluation. However, traditional two-dimensional (2D) monolayer cell models are unable to accurately predict drug activity in vivo, and animal models have species differences and ethical issues. Herein, a droplet-based 3D bioprinting strategy is established to construct lung cancer organoid arrays for drug evaluation. The bioink system is based on sodium alginate (SA, used to crosslink with Ca2+), hyaluronic acid (HA, used to improve gel viscoelasticity and printability), and arginine-glycine-aspartic acid peptide (RGD, used to improve cell adhesion). Hundreds of organoids with 3D multicellular spherical structures are produced in batches after post-printing culture. Compared with 2D monolayer culture models, 3D organoids show higher cell activity and functional expression of P-CK, ProSP-C, MUC1 and Caveolin-1, as well as higher anticancer drug resistance and IC50. This strategy will provide insights into the field of organoid modeling, high-throughput and personalized drug screening. [Display omitted] [ABSTRACT FROM AUTHOR]

Molecular classification of feline mammary carcinomas (FMC) from which specific behavioral patterns may be estimated has potential applications in veterinary clinical practice and in comparative oncology. In this perspective, the main goal of this study was to characterize both the clinical and the pathological features of the different molecular phenotypes found in a population of FMC (n = 102), using the broadly accepted IHC-based classification established by St. Gallen International Expert Consensus panel. The luminal B/HER2-negative subtype was the most common (29.4%, 30/102) followed by luminal B/HER2-positive subtype (19.6%, 20/102), triple negative basal-like (16.7%, 17/102), luminal A (14.7%, 15/102), triple negative normal-like (12.7%, 13/102) and finally, HER2-positive subtype (6.9%, 7/102). Luminal A subtype was significantly associated with smaller tumors ( p = 0.024) and with well differentiated ones ( p < 0.001), contrasting with the triple negative basal-like subtype, that was associated with larger and poorly differentiated tumors ( p < 0.001), and with the presence of necrotic areas in the tumoral lesion ( p = 0.003). In the survival analysis, cats with Luminal A subtype presented the highest survival time (mean OS = 943.6 days) and animals with triple negative basal-like subtype exhibited the lowest survival time (OS mean = 368.9 days). Moreover, two thirds (64%, 32/50) of the queens with multiple primary tumors showed different molecular subtypes in each carcinoma, revealing that all independent lesions should be analyzed in order to improve the clinical management of animals. Finally, the similarities between the subtypes of feline mammary tumors and human breast cancer, reveal that feline can be a valuable model for comparative studies. [ABSTRACT FROM AUTHOR]

As a synergistic drug combination, doxorubicin-loaded cisplatin crosslinked polysaccharide-based nanoparticles (Dex-SA-DOX-CDDP) have demonstrated enhanced antitumor efficacy and reduced systemic toxicity via optimized biodistribution, controlled drug release, prolonged blood circulation, and improved tolerability, compared to the non-crosslinked nanoparticles or free doxorubicin. Herein, we apply the Dex-SA-DOX-CDDP nanoparticles as an efficient antitumor agent to treat colorectal and breast tumors in three different in vivo models, i.e. subcutaneously implanted colorectal carcinoma, dimethylhydrazine-induced autochthonous colorectal carcinoma, and metastatic mammary carcinoma, which more closely simulate the natural milieu of the original tumor with intact pathological and immunological responses. Based on the properties of this combination in higher tumor accumulation and penetrating efficiency, the Dex-SA-DOX-CDDP nanoparticles significantly decreased the tumor sizes in CT26 cell line xenograft tumors compared to control. In addition, the affected animals' lifespan was significantly extended after the Dex-SA-DOX-CDDP treatment, in the autochthonous colon cancer model. Moreover, with the aid of iRGD, Dex-SA-DOX-CDDP could effectively block primary tumor growth and prevent the metastasis of 4T1 murine mammary carcinoma. In conclusion, Dex-SA-DOX-CDDP nanoparticles remarkably inhibit growth of colorectal carcinoma and metastasis of mammary carcinoma in vivo , which provides potential application as a safe and efficient antitumor agent in treatment of these cancers. [ABSTRACT FROM AUTHOR]

Abstract: Multicellular aggregates of cells, termed spheroids, are of interest for studying tumor behavior and for evaluating the response of pharmacologically active agents. Spheroids more faithfully reproduce the tumor macrostructure found in vivo compared to classical 2D monolayers. We present a method for embedding spheroids within collagen gels followed by quantitative and qualitative whole spheroid and single cell analyses enabling characterization over the length scales from molecular to macroscopic. Spheroid producing and embedding capabilities are demonstrated for U2OS and MDA-MB-231 cell lines, of osteosarcoma and breast adenocarcinoma origin, respectively. Finally, using the MDA-MB-231 tumor model, the chemotherapeutic response between paclitaxel delivery as a bolus dose, as practiced in the clinic, is compared to delivery within an expansile nanoparticle. The expansile nanoparticle delivery route provides a superior outcome and the results mirror those observed in a murine xenograft model. These findings highlight the synergistic beneficial results that may arise from the use of a drug delivery system, and the need to evaluate both drug candidates and delivery systems in the research and preclinical screening phases of a new cancer therapy development program. [Copyright &y& Elsevier]

Abstract: Experiments with cultures of human tumor cell lines, xenografts of human tumors into immunodeficient mice, and mouse models of human cancer are important tools in the development and testing of anti-cancer drugs. Tumors are complex structures composed of genetically and phenotypically heterogeneous cancer cells that interact in a reciprocal manner with the stromal microenvironment and the immune system. Modeling the complexity of human cancers in cell culture and in mouse models for preclinical testing is a challenge that has not yet been met although tremendous advances have been made. A combined approach of cell culture and mouse models of human cancer is most likely to predict the efficacy of novel anti-cancer treatments in human clinical trials. [Copyright &y& Elsevier]

Abstract: A mathematical model for leukemia therapy based on the Gompertzian law of cell growth is studied. It is assumed that the chemotherapeutic agents kill leukemic as well as normal cells. Effectiveness of the medicine is described in terms of a therapy function. Two types of therapy functions are considered: monotonic and non-monotonic. In the former case the level of the effect of the chemotherapy directly depends on the quantity of the chemotherapeutic agent. In the latter case the therapy function achieves its peak at a threshold value and then the effect of the therapy decreases. At any given moment the amount of the applied chemotherapeutic is regulated by a control function with a bounded maximum. Additionally, the total quantity of chemotherapeutic agent which can be used during the treatment process is bounded too. The problem is to find an optimal strategy of treatment to minimize the number of leukemic cells while at the same time retaining as many normal cells as possible. With the help of Pontryagin’s Maximum Principle it was proved that the optimal control function has at most one switch point in both monotonic and non-monotonic cases for most relevant parameter values. A control strategy called alternative is suggested. This strategy involves increasing the amount of the chemotherapeutical medicine up to a certain value within the shortest possible period of time, and holding this level until the end of the treatment. The comparison of the results from the numerical calculation using the Pontryagin’s Maximum Principle with the alternative control strategy shows that the difference between the values of cost functions is negligibly small. [Copyright &y& Elsevier]

Abstract: Three dimensional (3D) tumor spheroid models are becoming important biomedical tools for both fundamental and applied cancer studies, but current models do not account for different levels of cancer malignancy. Several studies have reported that the mechanical rigidity of a hydrogel plays a significant role in regulating the phenotypes of cancer cells adhered to the gel surface. This finding suggests that matrix rigidity should also modulate the malignancy of 3D tumor spheroids. However, the role of matrix stiffness is often confounded by concurrent changes in 3D matrix permeability. This study reports an advanced strategy to assemble 3D liver tumor spheroids with controlled intercellular organization, phenotypes, and angiogenic activities using hydrogels with controlled stiffness and minimal differences in molecular diffusivity. The elastic moduli of cell-encapsulated collagen gels were increased by stiffening interconnected collagen fibers with varied amounts of poly(ethylene glycol) di-(succinic acid N-hydroxysuccinimidyl ester). Interestingly, hepatocellular carcinoma cells encapsulated in a fat-like, softer hydrogel formed malignant cancer spheroids, while cells cultured in a liver-like, stiffer gel formed compact hepatoids with suppressed malignancy. Overall, both the hydrogel and the 3D tumor spheroids developed in this study will be greatly useful to better understand and regulate the emergent behaviors of various cancer cells. [Copyright &y& Elsevier]

Abstract: In vitro tumor models that mimic in vivo conditions may be ideal for screening anticancer drugs and their formulations and developing tumors in animal models. Three-dimensional (3-D) culture of cancer cells on polymeric scaffolds can be an option for such models. In the present study, porous poly(lactic acid-co-glycolic acid) (PLGA) microsphere was used both as a cancer cell culture substrate to expand cells and as a cancer cell transplantation vehicle for tumor construction in mice. MCF-7 cells cultured on porous PLGA microspheres in stirred suspension bioreactors expanded by 2.8-fold over seven days and maintained viability. At three months after inoculation with 2×106 cells/site, the tumor formation by MCF-7 cells cultured on microspheres was much more effective (4 tumors/5 mice) than its counterpart cultured on plates (1/5). More importantly, cell viability and metabolic activity were not significantly changed even after one freeze–thaw cycle of the 3-D culture. MCF-7 cells cultured on the microspheres and the cells in 3-D after cryopreservation were more resistant to doxorubicin than MCF-7 cells cultured on plates. [Copyright &y& Elsevier]

ING-1(heMAb), a human-engineered monoclonal antibody (MAb) that specifically targets the epithelial cell adhesion molecule (Ep-CAM), kills adenocarcinoma cells in vitro and inhibits tumor growth in vivo. In the current study, we evaluated the efficacy of ING-1(heMAb) in a murine model of cancer metastases. Mice received intravenous dosing of 1 mg/kg ING-1(heMAb), twice a week, starting on day 2 or day 5. A negative control group received 1 mg/kg human immunoglobulin G with the same dose frequency starting on day 2. A positive control group received weekly 100 mg/kg 5-flurouracil/leucovorin starting on day 2. ING-1(heMAb)/day 2 treatment significantly reduced both the number of visible tumor nodules in body cavities (P < .01) and the number of metastases on lung surfaces (P < .005). The treatment also resulted in a 91% reduction of micrometastases in lung tissues (P < .0001). Delaying ING-1(heMAb) treatment until day 5 caused 54% reduction in micrometastases (P < .005). Our results indicate that a number of parameters, including treatment starting day, dose level, and dose frequency, are critical in achieving the optimal efficacy of ING-1(heMAb). We conclude that ING-1(heMAb) effectively reduced tumor metastases in a murine cancer model. Immunotherapy with ING-1(heMAb) may be beneficial in treating human metastatic diseases. [ABSTRACT FROM AUTHOR]

Cancer patients often die from symptoms that manifest at a distance from any tumor. Mechanisms underlying these systemic physiological perturbations, called paraneoplastic syndromes, may benefit from investigation in non-mammalian systems. Using a non-metastatic Drosophila adult model, we find that malignant-tumor-produced cytokines drive widespread host activation of JAK-STAT signaling and cause premature lethality. STAT activity is particularly high in cells of the blood-brain barrier (BBB), where it induces aberrant BBB permeability. Remarkably, inhibiting STAT in the BBB not only rescues barrier function but also extends the lifespan of tumor-bearing hosts. We identify BBB damage in other pathological conditions that cause elevated inflammatory signaling, including obesity and infection, where BBB permeability also regulates host survival. IL-6-dependent BBB dysfunction is further seen in a mouse tumor model, and it again promotes host morbidity. Therefore, BBB alterations constitute a conserved lethal tumor-host interaction that also underlies other physiological morbidities. [Display omitted] • Fly tumors induce paraneoplastic opening of the BBB • BBB permeabilization by tumor-induced JAK/STAT activation accelerates host death • BBB also protects flies from a high-fat diet and non-pathogenic infections • A mouse tumor model disrupts the protective BBB in an IL-6-dependent manner Kim et al. use a fly cancer model to uncover a systemic effect of tumors in which inflammatory signaling permeabilizes the blood-brain barrier. Preventing barrier permeability allows flies to live longer with the same tumor burden, and key aspects of these data are recapitulated in a mouse tumor model. [ABSTRACT FROM AUTHOR]

In recent years, the tumor microenvironment (TME) has been a research hotspot, as it is composed of distinct cellular and non-cellular elements that may influence the diagnosis, prognosis, and treatment of breast cancer patients. Cancer cells are able to escape immune control through an immunoediting process which depends on complex communication networks between immune and cancer cells. Thus, a better understanding of the immune cell infiltrate in the breast cancer microenvironment is crucial for the development of more effective therapeutic approaches. In this review article, we overview the different actors that orchestrate the complexity of the TME, including tumor infiltrating lymphocytes (TILs), natural killer cells, tumor infiltrating dendritic cells (TIDCs), tumor associated macrophages (TAMs), tumor associated neutrophils (TANs), cancer associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), distinct pro-angiogenic factors and immune checkpoint biomarkers. Additionally, we summarize the recent advances in the TME of feline mammary carcinoma (FMC). FMC has been proposed as a reliable cancer model for the study of human breast cancer, as they share clinicopathological, histopathological and epidemiological features, as well as the pathways involved in cancer initiation and progression. [ABSTRACT FROM AUTHOR]

Two-dimensional (2D) in vitro cell cultures and laboratory animals have been used traditionally as the gold-standard preclinical cancer model systems. However, for cancer stem cell (CSC) studies, they exhibit notable limitations on simulating native environment, which depreciate their translatability for clinical development purposes. In this study, different three-dimensional (3D) printing platforms were used to establish novel 3D cell cultures enriched in CSCs from non-small cell lung cancer (NSCLC) patients and cell lines. Rigid scaffolds with an elevated compressive modulus and uniform pores and channels were produced using different filaments. Hydrogel-based scaffolds were printed with a more irregular distribution of pores and a lower compressive modulus. As a 3D model of reference, suspension spheroid cultures were established. Therein, cancer cell lines exhibited enhanced proliferation profiles on rigid scaffolds compared to the same cells grown on either hydrogel scaffolds or tumor spheres. Meanwhile, primary cancer cells grew considerably better on hydrogel scaffolds or in tumor sphere culture, compared to cells grown on rigid scaffolds. Gene expression analysis confirmed that tumor spheres and cells seeded on hydrogel scaffolds significantly overexpress most of stemness and invasion promoters tested compared to control cells grown in 2D culture. A different phenomenon was observed within cells growing on the rigid scaffolds, where fewer significant variations in gene expression were detected. Our findings provide strong evidence for the advantageous usage of 3D printed models, especially those which use GelMA-PEGDA hydrogels as the primary scaffold material, for studying lung CSCs. The results demonstrated that the 3D printed scaffolds were better to mimic tumor complexity and regulate cancer cell behavior than in vivo 2D culture models. Unlabelled Image • Fused deposition modeling and stereolithography technologies can be used for fabricating 3D cell culture systems. • Primary lung cancer cells grow considerably better on hydrogel scaffolds or in tumor sphere culture than in rigid scaffolds. • Cells grown on scaffolds have a significant increase in CSCs-related gene expression, especially in hydrogel-based ones. • 3D printing constitutes a potential tool for CSCs characterization. [ABSTRACT FROM AUTHOR]

In this paper we develop and analyze a three dimensional cancer model based on the chaotic behavior. Firstly we construct stochastic environment because of parameters random essence, and introduce chaotic cancer model in stochastic form. Then we prove the uniqueness and existence of solution on the stochastic system. Moreover, the equilibria of the system is considered. Finally, some numerical simulations are carried out to show the efficiency and adaptation of our model as a function of time. • Providing chaotic cancer model in stochastic form. • Investigation on the uniqueness and existence solution of the proposed model. • Numerical implementation and comparison to evaluate the performance and compatibility. [ABSTRACT FROM AUTHOR]

Three dimensional (3D) bioprinting of multiple cell types within optimised extracellular matrices has the potential to more closely model the 3D environment of human physiology and disease than current alternatives. In this study, we used a multi-nozzle extrusion bioprinter to establish models of glioblastoma made up of cancer and stromal cells printed within matrices comprised of alginate modified with RGDS cell adhesion peptides, hyaluronic acid and collagen-1. Methods were developed using U87MG glioblastoma cells and MM6 monocyte/macrophages, whilst more disease relevant constructs contained glioblastoma stem cells (GSCs), co-printed with glioma associated stromal cells (GASCs) and microglia. Printing parameters were optimised to promote cell-cell interaction, avoiding the 'caging in' of cells due to overly dense cross-linking. Such printing had a negligible effect on cell viability, and cells retained robust metabolic activity and proliferation. Alginate gels allowed the rapid recovery of printed cell protein and RNA, and fluorescent reporters provided analysis of protein kinase activation at the single cell level within printed constructs. GSCs showed more resistance to chemotherapeutic drugs in 3D printed tumour constructs compared to 2D monolayer cultures, reflecting the clinical situation. In summary, a novel 3D bioprinting strategy is developed which allows control over the spatial organisation of tumour constructs for pre-clinical drug sensitivity testing and studies of the tumour microenvironment. [ABSTRACT FROM AUTHOR]

Representative in vitro models that mimic the native bone tumor microenvironment are warranted to support the development of more successful treatments for bone metastases. Here, we have developed a primary cell 3D model consisting of a human osteoblast-derived tissue-engineered construct (hOTEC) indirectly co-cultured with patient-derived prostate cancer xenografts (PDXs), in order to study molecular interactions in a patient-derived microenvironment context. The engineered biomimetic microenvironment had high mineralization and embedded osteocytes, and supported a high degree of cancer cell osteomimicry at the gene, protein and mineralization levels when co-cultured with prostate cancer PDXs from a lymph node metastasis (LuCaP35) and bone metastasis (BM18) from patients with primary prostate cancer. This fully patient-derived model is a promising tool for the assessment of new molecular mechanisms and as a personalized pre-clinical platform for therapy testing for patients with prostate cancer bone metastases. [ABSTRACT FROM AUTHOR]