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Cancer is a major stress for public well‐being and is the most dreadful disease. The models used in the discovery of cancer treatment are continuously changing and extending toward advanced preclinical studies. Cancer models are either naturally existing or artificially prepared experimental systems that show similar features with human tumors though the heterogeneous nature of the tumor is very familiar. The choice of the most fitting model to best reflect the given tumor system is one of the real difficulties for cancer examination. Therefore, vast studies have been conducted on the cancer models for developing a better understanding of cancer invasion, progression, and early detection. These models give an insight into cancer etiology, molecular basis, host tumor interaction, the role of microenvironment, and tumor heterogeneity in tumor metastasis. These models are also used to predict novel cancer markers, targeted therapies, and are extremely helpful in drug development. In this review, the potential of cancer models to be used as a platform for drug screening and therapeutic discoveries are highlighted. Although none of the cancer models is regarded as ideal because each is associated with essential caveats that restraint its application yet by bridging the gap between preliminary cancer research and translational medicine. However, they promise a brighter future for cancer treatment., In vitro and in vivo Animal models have been extensively used in cancer research. At present omics data and computational models are in practice. Each model has it own pros and cons.

Programmed cell death ligand‐1 (PD‐L1) is a ligand for programmed cell death‐1 (PD‐1) that negatively regulates T‐cell activation and plays a crucial role in suppressing anti‐tumor host immunity. Although PD‐L1 is a promising immunotherapy target in various cancers, including urothelial carcinoma (UC), the prognostic significance of PD‐L1 in UC is unclear. As platelets help protect tumor cells from immune elimination in the circulatory system, we hypothesized that tumor PD‐L1 and circulating platelets might synergistically promote tumor metastasis, and that the prognostic significance of PD‐L1 might vary according to platelet count. We immunohistochemically examined tumor PD‐L1 expression in 271 patients with upper tract UC, which revealed PD‐L1 positivity in 31 of 271 cases (11%). The associations of tumor PD‐L1 expression with outcomes varied among patients with high or low platelet counts (Pinteraction

The 21st annual Cancer Research Institute (CRI) cancer immunotherapy symposium, entitled “Dynamics of Host–Tumor Interaction,” was held in New York City from September 30 through October 2, 2013. The symposium comprised 27 presentations, organized into five sessions and exploring such topics as the role of chronic inflammation in creating a protumorigenic microenvironment, the interactions between the cancer stroma and immune cells in trafficking and cancer metastasis, the role of the host microbiota in immune responses to cancer, and the interactions between cancer cells and immunoregulatory elements, including regulatory T cells and T-cell checkpoint proteins. The conference began with a keynote address by Michael Karin, recipient of the 2013 Coley Award, who discussed the role of inflammation as a Janus-faced process in the body's fight against cancer—both tumor destroying and tumor promoting. The conference concluded with a session on therapeutics and translational research aimed at improving existing cancer immunotherapies. Cancer Immunol Res; 2(2); 105–11. ©2014 AACR.

The purpose of this study is to investigate the effects of exercise on cancer progression, metastasis, and underlying mechanisms in an orthotopic model of murine prostate cancer. C57BL/6 male mice (6–8 wk of age) were orthotopically injected with transgenic adenocarcinoma of mouse prostate C-1 cells (5 × 105) and randomly assigned to exercise ( n = 28) or a non-intervention control ( n = 31) groups. The exercise group was given voluntary access to a wheel 24 h/day for the duration of the study. Four mice per group were serially killed on days 14, 31, and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Before death, MRI was performed to assess tumor blood perfusion. Primary tumor growth rate was comparable between groups, but expression of prometastatic genes was significantly modulated in exercising animals with a shift toward reduced metastasis. Exercise was associated with increased activity of protein kinases within the MEK/MAPK and PI3K/mTOR signaling cascades with subsequent increased intratumoral protein levels of HIF-1α and VEGF. This was associated with improved tumor vascularization. Multiplex ELISAs revealed distinct reductions in plasma concentrations of several angiogenic cytokines in the exercise group, which was associated with increased expression of angiogenic and metabolic genes in the skeletal muscle. Exercise-induced stabilization of HIF-1α and subsequent upregulation of VEGF was associated with “productive” tumor vascularization with a shift toward suppressed metastasis in an orthotopic model of prostate cancer.

Adipose tissue has recently emerged as a driver of tumorigenesis, as adipose-associated factors enhance tumor growth and development. Here we investigated for the first time direct crosstalk between visceral adipose tissue (VAT) and tumor tissues in colorectal cancer (CRC) patients. We analyzed paired transcriptomic profiles of tissues and systemic inflammatory biomarkers among CRC patients to elucidate potential mechanisms and molecular signals driving the host-tumor interaction. Paired presurgery blood and tumor adjacent VAT, colorectal tumor and mucosa tissue samples collected during surgery were obtained from 47 Caucasian patients diagnosed with microsatellite-stable primary CRC enrolled in the ColoCare Study. Clinical/demographic information, and lifestyle-related risk factors, were reported. VAT was quantified by computed tomography. RNA was extracted from VAT, colorectal tumor and mucosa tissues, analyzed using HumanHT-12 Expression BeadChips, processed, and validated. Serum-based assays were conducted in 46 of 47 patients for systemic inflammatory markers with the Mesoscale Discovery Platform. High PTGS2 tumor expression was associated with 131 significantly altered VAT genes, of which 85.5% were upregulated. A significant upstream regulator of dysregulated VAT genes was SAA1. Investigation of circulating inflammatory biomarkers corroborated these transcriptomic findings, as patients with high PTGS2 tumor expression were also significantly more likely to have higher serum-based SAA levels. The differential expression of PPAR-γ in VAT identified 284 significantly altered tumor genes. 71.8% of tumor genes were upregulated in association with higher PPAR-γ VAT expression. Differentially expressed tumor genes were enriched in functional cellular movement. Inflammatory biomarkers in patient sera showed marginally significant differences for soluble ICAM-1 in association with differential PPAR-γ VAT expression. Overlap of the 131 altered VAT genes associated with differential PTGS2 tumor expression with the 284 dysregulated tumor genes associated with differential PPAR-γ VAT expression identified 15 common genes. Gene set enrichment analysis demonstrated that phenotypes associated with these genes in humans included cancer invasiveness signatures from tumor microenvironment interactions. Our multi-omics profiling of paired tissue transcriptomics and systemic inflammatory biomarkers from CRC patients established a bidirectional link between VAT and colorectal tumor tissue. We have demonstrated that this direct crosstalk activates signaling cascades to promote proinflammatory interactions and metabolic reprogramming. Future efforts to develop mechanism-based interventions that disrupt these molecular signals at the nexus of VAT-tumor crosstalk may improve obesity-driven CRC prevention and control. Citation Format: Andreana N. Holowatyj, Mariam Haffa, Tengda Lin, Biljana Gigic, Jennifer Ose, Christy Warby, Caroline Himbert, Clare Abbenhardt, Juergen Boehm, Magnus von Knebel Doeberitz, Nina Habermann, Esther Herpel, Hans-Ulrich Kauczor, Matthias Kloor, Johanna Nattenmüller, Peter Schirmacher, Martin Schneider, Petra Schrotz-King, Thomas Simon, Alexis Ulrich, Laura Bowers, Stephen D. Hursting, Cornelia M. Ulrich. Crosstalk between visceral adipose and tumor tissue in colorectal cancer patients: Molecular signals driving host-tumor interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5249.

Background Children with advanced-stage neuroblastoma (NB) traditionally experience poor outcomes. Because early detection of advanced-stage disease may impact survival, finding new targets for early diagnosis is crucial. Evidence suggests the tumor microenvironment may have profound effects on cancer progression. Methods As little is known concerning the NB-host microenvironment, this study applied proteomic techniques, two-dimensional polyacrylamide gel electrophoresis (2D PAGE) combined with matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry to determine protein differences between cell cultured NB and tumors grown in mice for 2, 4, and 5 wk. Results We found an increase in proteins in cultured NB compared with implanted mouse tumors during tumor progression. Additionally, analyzing in vivo tumors to cultured NB, we observed less expressed proteins. However, 16 out of 19 proteins were of mouse origin, thus inferring host-derived factors contributing to tumor growth. Conclusion We show that the dynamic relationship between NB and host microenvironment is important for tumor growth and better understanding of this milieu maybe relevant towards finding unique approaches for identifying advanced-stage disease.

This review considers the various roles of the TGF-beta system in mammary carcinogenesis, tumor progression, and cellular responses to therapeutic measures. The paradigm that has evolved from the work of many investigators suggests that loss of tumor cell responsiveness to the effects of TGF-beta can result in a crucial shift in the net effect of TGF-beta within the context of the tumor-host interaction. Principal elements of host-tumor interactions in which this shift may play out, including immune suppression, angiogenesis, and modification of the surrounding extracellular matrix by tumor cells, are potentially amenable to manipulation. Additional effects of TGF-beta, such as suggested by reports of its ability to alter the drug resistance of tumor cells and the drug sensitivity of normal tissues, suggest that appropriate molecular intervention designed to affect the TGF-beta system might constitute an effective therapeutic strategy.

Cell migration is fundamental to many aspects of biology, including development, wound healing, the cellular responses of the immune system, and metastasis of tumor cells. Migration has been studied on glass coverslips in order to make cellular dynamics amenable to investigation by light microscopy. However, it has become clear that many aspects of cell migration depend on features of the local environment including its elasticity, protein composition, and pore size, which are not faithfully represented by rigid two dimensional substrates such as glass and plastic 1. Furthermore, interaction with other cell types, including stromal fibroblasts 2 and immune cells 3, has been shown to play a critical role in promoting the invasion of cancer cells. Investigation at the molecular level has increasingly shown that molecular dynamics, including response to drug treatment, of identical cells are significantly different when compared in vitro and in vivo 4. Ideally, it would be best to study cell migration in its naturally occurring context in living organisms, however this is not always possible. Intermediate tissue culture systems, such as cell derived matrix, matrigel, organotypic culture (described here) tissue explants, organoids, and xenografts, are therefore important experimental intermediates. These systems approximate certain aspects of an in vivo environment but are more amenable to experimental manipulation such as use of stably transfected cell lines, drug treatment regimes, long term and high-resolution imaging. Such intermediate systems are especially useful as proving grounds to validate probes and establish parameters required to image the dynamic response of cells and fluorescent reporters prior to undertaking imaging in vivo 5. As such, they can serve an important role in reducing the need for experiments on living animals.

Understanding the cellular, biochemical and immunological ramifications of the host-tumor interaction at both the local tumor level and the systemic level is key to the design of successful therapeutic modalities for human cancers. The participation of cytokines in both the local and systemic aspects of the host-tumor interaction has been extensively established. Indeed, there is now not only a vast literature on the involvement of cytokines in the biology of host-tumor interaction, but also on the therapeutic use in human cancer of cytokines such as the various interferons, interleu-kins, hematopoietic growth factors, and an ever-increasing list of new cytokines. These cytokines (or ‘biological response modifiers’) have been introduced into anti-cancer regimens, either for their direct anti-tumor effects on neoplastic cell elements, or for their indirect anti-tumor effects through enhancement of the host’s immunological response to cancer or through enhancement of the recovery of the host after the use of other bone marrow suppressive anti-cancer agents. Effective therapeutic use of cytokines in human cancer (for example of interferon-a) is now definitely established.

Adequate parenteral nutritional support improves nutritional status in cancer patients, but its effect on tumor growth remains controversial. Using a transplantable mammary adenocarcinoma in a rat-TPN model, the relative effect of different exogenous intravenous nutrients on tumor growth and host maintenance was studied. Relative to chow controls, starvation increased host depletion without reducing tumor growth. Adequate carbohydrate calories alone neither improved host maintenance nor stimulated tumor growth, yet adequate amino acids alone did improve host maintenance but also stimulated tumor growth. Adequate amino acids and carbohydrates given simultaneously maximized both host maintenance and tumor growth. In contrast, an isocaloric, isonitrogenous, intravenous diet providing non-nitrogenous calories as fat promoted host maintenance equivalent to carbohydrate-based TPN with no tumor stimulation. This apparent differential utilization of fat calories by normal and malignant cells may permit manipulation of the relative benefit of parenteral nutrition to host or to tumor, permitting host repletion without tumor stimulation or alternatively tumor stimulation at appropriate times to increase sensitivity to phase-specific antineoplastic therapy.

The Dunning R3327 tumor sublines in the Fischer-Copenhagen F1 rat provide a spectrum of transplantable prostate adenocarcinomas for the study of host-tumor interactions. The tumor can be transplanted with both fresh and cryopreserved cell suspensions. The F1 rat is an appropriate animal for immunological studies based on humoral and cellular immune responses. Preliminary evidence of the host-tumor relationship in the F1 rat indicates that purified membrane preparations induced a specific cytotoxic population of lymphocytes.

The expression of products encoded by the major histocompatibility complex (MHC) on tumor cells has recently been studied extensively. It has been found that many malignant tumor cells have their MHC antigens ‘switched-off’ but that these antigens are re-expressed following DNA-mediated gene transfer, with increased tumor immunogenicity as a result and the consequence that these ‘transformed’ tumor cells are rejected in vivo.: This review will discuss approaches that have been taken to induce strong tumor-specific immunity by the manipulation of MHC expression on tumor cells.

The environment affects living organisms during their whole life time. But endogenous facts provide long term influences on the organisms also. The single steps of such influences may be harmless (and in general they are), but the continued stimulus can harm the tissue cells to the point of transformation and, finally, neoplastic disease. The time frame, depending on tissues and stimuli, can be as short as a few months or extend to last for decades. Dormant tumor cells are a special case. In 1942, I. Berenblum introduced the concept of two-stage carcinogenesis, separating the initiator and the promoter during carcinogenesis. But it sees the problem only from the point of view of the full active carcinogen and the promoting compounds. However, if we regard neoplastic growth not only as tumor production, but also include such topics as host tumor interaction, metabolic interaction, immunology factors, ectopic hormones, and the development of metastasis, then the neoplastic development becomes a chain event.

Understanding mechanisms mediating tumor metastasis is crucial for diagnostic and therapeutic targeting. Here, we take advantage of a transparent embryonic zebrafish xenograft model (eZXM) to visualize and track metastatic cells in real time using selective plane illumination microscopy (SPIM) for up to 30 h. Injected human leukemic and breast cancer cells exhibited cell-type specific patterns of intravascular distribution with leukemic cells moving faster than breast cancer cells. Tracking of tumor cells from high-resolution images revealed acute differences in intravascular speed and distance covered by cells. While the majority of injected breast cancer cells predominantly adhered to nearby vasculature, about 30% invaded the non-vascularized tissue, reminiscent of their metastatic phenotype. Survival of the injected tumor cells appeared to be partially inhibited and time-lapse imaging showed a possible role for host macrophages of the recipient embryos. Leukemic cell dissemination could be effectively blocked by pharmacological ROCK1 inhibition using Fasudil. These observations, and the ability to image several embryos simultaneously, support the use of eZXM and SPIM imaging as a functional screening platform to identify compounds that suppress cancer cell spread and invasion.