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• W3108142058 abstract "Recent studies have begun to highlight the diverse and tumor-specific microbiomes across multiple cancer types. We believe this work raises the important question of whether the classical “Hallmarks of Cancer” should be expanded to include tumor microbiomes. To answer this question, the causal relationships and co-evolution of these microbiotic tumor ecosystems must be better understood. Because host-microbe interactions should be studied in a physiologically relevant context, animal models have been preferred. Yet these models are often poor mimics of human tumors and are difficult to interrogate at high spatiotemporal resolution. We believe that in vitro tissue engineered platforms could provide a powerful alternative approach that combines the high-resolution of in vitro studies with a high degree of physiological relevance. This review will focus on tissue engineered approaches to study host-microbe interactions and to establish their role as an emerging hallmark of cancer with potential as a therapeutic target. Recent studies have begun to highlight the diverse and tumor-specific microbiomes across multiple cancer types. We believe this work raises the important question of whether the classical “Hallmarks of Cancer” should be expanded to include tumor microbiomes. To answer this question, the causal relationships and co-evolution of these microbiotic tumor ecosystems must be better understood. Because host-microbe interactions should be studied in a physiologically relevant context, animal models have been preferred. Yet these models are often poor mimics of human tumors and are difficult to interrogate at high spatiotemporal resolution. We believe that in vitro tissue engineered platforms could provide a powerful alternative approach that combines the high-resolution of in vitro studies with a high degree of physiological relevance. This review will focus on tissue engineered approaches to study host-microbe interactions and to establish their role as an emerging hallmark of cancer with potential as a therapeutic target. The involvement of tumor-specific bacteria, collectively termed the tumor microbiome, has garnered significant attention as a key potential regulator of the well-established “Hallmarks of Cancer.” These hallmarks include deregulated proliferation, replicative immortality, genomic instability, evasion of growth suppression, avoidance of immune surveillance, chronic inflammation, angiogenic induction, and the activation of metastatic pathways (Hanahan and Weinberg, 2011Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (40071) Google Scholar). Bacteria and their secreted metabolites have been implicated in influencing most, if not all, these host factors (Fulbright et al., 2017Fulbright L.E. Ellermann M. Arthur J.C. The microbiome and the hallmarks of cancer.PLoS Pathog. 2017; 13: e1006480Crossref PubMed Scopus (71) Google Scholar). Although many in vitro models have helped elucidate mechanisms related to tumorigenesis, there are only limited models that are amenable to directly investigate host-microbe interactions, and far fewer in the context of cancer. Similarly, although animal models have been an indispensable tool in microbiome studies associated with cancer, they exhibit significant variability in their resident bacterial species and immune profiles when compared with humans. To address these issues, we believe that tissue engineering provides a unique opportunity to bridge the gap between in vitro and animal models in analyzing these host-microbe interactions in the tumor microenvironment (TME) that are so critical for tumor progression and therapy response. Tissue engineered models developed from human cells not only maintain the genetic constitution of the host but also do so in a physiologically relevant three-dimensional structure that consists of multiple, differentiated cell types functioning in synergism as in native tissue. Furthermore, these platforms are amenable to interrogation at high spatiotemporal resolutions, which is just not possible in larger animal models. For example, one can use these platforms to study the role of individual bacterial interactions with the host to distinguish correlation from causation in microbial impacts on cancer, which are normally obscured by multiple confounding factors within animal models. Current tissue engineered platforms that have been developed to study host-microbiome interactions are predominantly based on recreating the gut epithelium, which harbors the majority of microorganisms in the human body (Sender et al., 2016Sender R. Fuchs S. Milo R. Revised estimates for the number of human and bacteria cells in the body.PLoS Biol. 2016; 14: e1002533Crossref PubMed Scopus (2021) Google Scholar). Historically, there have been several challenges limiting the development of these platforms. Each tissue type has its own specific engineering challenges including cellular spatial constraints, physical forces, biochemical cues, and cell growth and differentiation capacities that need to be addressed, and hence, a personalized and experimentally tailored approach is preferred to develop each tissue type. The convergence of technologies from multiple disciplines has enabled the possibility to incorporate advanced sensors and imaging modalities for real-time monitoring of oxygen, pH, barrier permeability, and other biological parameters to recapitulate and analyze host-microbial interactions. In this review, we highlight the latest insights derived from 2D, 3D, and organ-on-chip platforms that have been used to investigate the interactions within the host-microbial consortia and explore the potential for adapting these platforms to advance our understanding of the tumor microbiome. The human microbiome, consisting of trillions of microorganisms co-existing within the human body, has an enormous impact on maintaining health and normal physiology (Brestoff and Artis, 2013Brestoff J.R. Artis D. Commensal bacteria at the interface of host metabolism and the immune system.Nat. Immunol. 2013; 14: 676-684Crossref PubMed Scopus (550) Google Scholar; Fan and Pedersen, 2020Fan Y. Pedersen O. Gut microbiota in human metabolic health and disease.Nat. Rev. Microbiol. 2020; : 1-17https://doi.org/10.1038/s41579-020-0433-9Crossref PubMed Scopus (563) Google Scholar). A dysbiotic microbiome adversely impacts homeostasis, which leads to a number of unfavorable outcomes including inflammatory diseases, cardiovascular disease, obesity, and diabetes and can even potentiate cancer initiation and progression (Udayasuryan et al., 2019Udayasuryan B. Slade D.J. Verbridge S.S. Microfluidics in Microbiome and Cancer Research. John Wiley & Sons, Ltd, 2019Google Scholar; Xavier et al., 2020Xavier J.B. Young V.B. Skufca J. Ginty F. Testerman T. Pearson A.T. Macklin P. Mitchell A. Shmulevich I. Xie L. et al.The cancer microbiome: distinguishing direct and indirect effects requires a systemic view.Trends Cancer. 2020; 6: 192-204Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Studies of the microbiome often characterize microbial compositional alterations in disease conditions (Durack and Lynch, 2019Durack J. Lynch S.V. The gut microbiome: relationships with disease and opportunities for therapy.J. Exp. Med. 2019; 216: 20-40Crossref PubMed Scopus (259) Google Scholar). However, the inherent complexity and variability in these experiments makes it challenging to derive meaningful conclusions on the microbes' direct impact on cancer progression. This is further compounded by the fact that the gut microbiome can play a dual role by being both tumor promoting and tumor restricting. A striking recent example within a mouse model revealed that p53-disabling mutations exhibited divergent effects based on the location of the cells within the gut and its spatially segregated microbial composition, behaving oncogenic distally, but tumor-suppressive proximally (Kadosh et al., 2020Kadosh E. Snir-Alkalay I. Venkatachalam A. May S. Lasry A. Elyada E. Zinger A. Shaham M. Vaalani G. Mernberger M. et al.The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic.Nature. 2020; 586: 133-138Crossref PubMed Scopus (103) Google Scholar). That microbiotic residents may regulate the action of such an archetypal tumor suppressor gene as p53 suggests that we are only scratching the surface of the role of tumor-localized microbiomes in cancer. Our understanding of the role of microbes in tumor progression has been advanced by next-generation sequencing, specifically 16S rRNA sequencing, which has uncovered reproducible microbial signatures within a multitude of tumors. Most recently, Nejman et al. identified distinct intracellular bacteria within cancer and immune cells in 1,526 tumor samples (consisting of a mix of flash frozen and formalin-fixed paraffin-embedded samples) and their adjacent tissues of seven cancer types: breast, lung, ovary, pancreas, melanoma, bone, and brain tumors (Nejman et al., 2020Nejman D. Livyatan I. Fuks G. Gavert N. Zwang Y. Geller L.T. Rotter-Maskowitz A. Weiser R. Mallel G. Gigi E. et al.The human tumor microbiome is composed of tumor type–specific intracellular bacteria.Science. 2020; 368: 973-980Crossref PubMed Scopus (404) Google Scholar). The number of bacterial species detected in most of the tumors averaged ~9. Interestingly, breast tissue was identified as having the most diverse tumor microbiome with an average of 16.4 species per sample (Figures 1A–1C ). In our own work, we previously examined the impact of molecules secreted by a bacterium that had been identified as present in the breast TME (Balhouse et al., 2017Balhouse B.N. Patterson L. Schmelz E.M. Slade D.J. Verbridge S.S. N-(3-oxododecanoyl)-L-homoserine lactone interactions in the breast tumor microenvironment: implications for breast cancer viability and proliferation in vitro.PLoS One. 2017; 12: e0180372Crossref PubMed Scopus (11) Google Scholar). This more recent finding by Nejman et al. provides further evidence that local tumor microbiomes may play a critical role in multiple cancer types. However, critical interactions and modes of tumor regulation have largely only been studied in the context of gastrointestinal cancers. Building tissue engineered models recapitulating the TME of different cancer types that have the ability to support the growth and maintenance of tumor microbiomes will be a key next step to investigate the specific roles of microbes in cancer. Many seminal studies have shown that individual microbial species play a role in the onset and progression of multiple cancers. Well-known examples include Helicobacter pylori in gastric cancer (Correa and Piazuelo, 2011Correa P. Piazuelo M.B. Helicobacter pylori infection and gastric adenocarcinoma.US Gastroenterol. Hepatol. Rev. 2011; 7: 59-64PubMed Google Scholar; Uemura et al., 2001Uemura N. Okamoto S. Yamamoto S. Matsumura N. Yamaguchi S. Yamakido M. Taniyama K. Sasaki N. Schlemper R.J. Helicobacter pylori infection and the development of gastric cancer.N. Engl. J. Med. 2001; 345: 784-789Crossref PubMed Scopus (3569) Google Scholar) and MALT lymphoma (Farinha and Gascoyne, 2005Farinha P. Gascoyne R.D. Helicobacter pylori and MALT lymphoma.Gastroenterology. 2005; 128: 1579-1605Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar), Salmonella typhi in gallbladder cancer (Ferreccio, 2012Ferreccio C. Salmonella typhi and gallbladder cancer.in: Khan A.A. Bacteria and Cancer. Springer Netherlands, Dordrecht2012: 117-137Crossref Scopus (8) Google Scholar), Streptococcus bovis in colon cancer (Boleij et al., 2009Boleij A. Schaeps R.M.J. Tjalsma H. Association between Streptococcus bovis and colon cancer.J. Clin. Microbiol. 2009; 47: 516Crossref PubMed Scopus (50) Google Scholar), and Chlamydia pneumoniae in lung cancer (Zhan et al., 2011Zhan P. Suo L. Qian Q. Shen X. Qiu L.-X. Yu L. Song Y. Chlamydia pneumoniae infection and lung cancer risk: a meta-analysis.Eur. J. Cancer Oxf. Engl. 2011; 1990: 742-747Abstract Full Text Full Text PDF Scopus (63) Google Scholar). Several associations including the discovery of Fusobacterium nucleatum within colorectal cancer (CRC) (Kostic et al., 2012Kostic A.D. Gevers D. Pedamallu C.S. Michaud M. Duke F. Earl A.M. Ojesina A.I. Jung J. Bass A.J. Tabernero J. et al.Genomic analysis identifies association of Fusobacterium with colorectal carcinoma.Genome Res. 2012; 22: 292-298Crossref PubMed Scopus (1130) Google Scholar), high abundance of Acidovorax temporans in lung cancers with TP53 mutations (Greathouse et al., 2018Greathouse K.L. White J.R. Vargas A.J. Bliskovsky V.V. Beck J.A. von Muhlinen N. Polley E.C. Bowman E.D. Khan M.A. Robles A.I. et al.Interaction between the microbiome and TP53 in human lung cancer.Genome Biol. 2018; 19: 123Crossref PubMed Scopus (129) Google Scholar), and variations in the oral and gut microbiome of patients with melanoma undergoing PD-1 immunotherapy (Gopalakrishnan et al., 2018Gopalakrishnan V. Spencer C.N. Nezi L. Reuben A. Andrews M.C. Karpinets T.V. Prieto P.A. Vicente D. Hoffman K. Wei S.C. et al.Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients.Science. 2018; 359: 97-103Crossref PubMed Scopus (1932) Google Scholar) indicate a correlative role of the human microbiome with cancer. In addition, intracellular organisms can also directly impact chemotherapy regimens. For example, Gammaproteobacteria within pancreatic ductal adenocarcinoma can metabolize the chemotherapeutic drug gemcitabine (Geller et al., 2017Geller L.T. Barzily-Rokni M. Danino T. Jonas O.H. Shental N. Nejman D. Gavert N. Zwang Y. Cooper Z.A. Shee K. et al.Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.Science. 2017; 357: 1156-1160Crossref PubMed Scopus (583) Google Scholar). The most dramatic consequence is the lowering of patient survival with the presence of these bacteria in the tumor. Microbes within the TME can induce a mix of direct and indirect effects to impact tumorigenesis. From prior work largely on CRC, it is known that bacteria within tumors can cause chronic inflammation or produce and release toxins that impact the cell cycle and induce DNA damage that leads to tumor-initiating or -promoting mutations (van Elsland and Neefjes, 2018van Elsland D. Neefjes J. Bacterial infections and cancer.EMBO Rep. 2018; 19: e46632PubMed Google Scholar). Microbes in the TME can also influence tissue remodeling and deregulate mucosal immunity, creating a favorable niche for tumor cells to expand and migrate (Fares et al., 2020Fares J. Fares M.Y. Khachfe H.H. Salhab H.A. Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited.Signal. Transduct. Target. Ther. 2020; 5: 1-17Crossref PubMed Scopus (375) Google Scholar). Moreover, bacteria can induce epigenetic alterations upon gaining intracellular access that can activate dormant tumor-promoting genes (Niller and Minarovits, 2016Niller H.H. Minarovits J. Patho-epigenetics of infectious diseases caused by intracellular bacteria.in: Minarovits J. Niller H.H. Patho-Epigenetics of Infectious Disease. Springer International Publishing, 2016: 107-130Crossref Scopus (20) Google Scholar). As a prototypical oncomicrobe that has received significant attention, F. nucleatum's involvement in CRC has been extensively characterized in recent years and serves as a prime example to highlight the multiple mechanisms pathogens can use to impact cancer progression. High Fusobacterium levels in tumors correlate with decreased patient survival in CRC (Kunzmann et al., 2019Kunzmann A.T. Proença M.A. Jordao H.W. Jiraskova K. Schneiderova M. Levy M. Liska V. Buchler T. Vodickova L. Vymetalkova V. et al.Fusobacterium nucleatum tumor DNA levels are associated with survival in colorectal cancer patients.Eur. J. Clin. Microbiol. Infect. Dis. 2019; 38: 1891-1899Crossref PubMed Scopus (20) Google Scholar; Mima et al., 2016Mima K. Nishihara R. Qian Z.R. Cao Y. Sukawa Y. Nowak J.A. Yang J. Dou R. Masugi Y. Song M. et al.Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.Gut. 2016; 65: 1973-1980Crossref PubMed Scopus (431) Google Scholar), pancreatic cancer (Mitsuhashi et al., 2015Mitsuhashi K. Nosho K. Sukawa Y. Matsunaga Y. Ito M. Kurihara H. Kanno S. Igarashi H. Naito T. Adachi Y. et al.Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis.Oncotarget. 2015; 6: 7209-7220Crossref PubMed Scopus (175) Google Scholar), and esophageal cancers (Yamamura et al., 2016Yamamura K. Baba Y. Nakagawa S. Mima K. Miyake K. Nakamura K. Sawayama H. Kinoshita K. Ishimoto T. Iwatsuki M. et al.Human microbiome Fusobacterium nucleatum in esophageal cancer tissue is associated with prognosis.Clin. Cancer Res. 2016; 22: 5574-5581Crossref PubMed Scopus (182) Google Scholar). An oral commensal microbe, it has been associated with periodontitis, gingivitis, and multiple extra-oral diseases. It's surface adhesin, Fap2, targets the host carbohydrate Gal/Gal-NAc (Abed et al., 2016Abed J. Emgård J.E.M. Zamir G. Faroja M. Almogy G. Grenov A. Sol A. Naor R. Pikarsky E. Atlan K.A. et al.Fap2 mediates fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc.Cell Host Microbe. 2016; 20: 215-225Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar; Parhi et al., 2020Parhi L. Alon-Maimon T. Sol A. Nejman D. Shhadeh A. Fainsod-Levi T. Yajuk O. Isaacson B. Abed J. Maalouf N. et al.Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression.Nat. Commun. 2020; 11: 3259Crossref PubMed Scopus (81) Google Scholar) that is overexpressed on many cancers (Shamsuddin et al., 1995Shamsuddin A.M. Tyner G.T. Yang G.Y. Common expression of the tumor marker D-galactose-beta-[1-->3]-N-acetyl-D-galactosamine by different adenocarcinomas: evidence of field effect phenomenon.Cancer Res. 1995; 55: 149-152PubMed Google Scholar) and may explain how these bacteria are found in higher abundance in CRC compared with the adjacent healthy tissue. Strikingly, it was found that Fusobacteria can travel intracellularly within a migrating host CRC cell leading to bacterial seeding at distant sites such as the liver (Bullman et al., 2017Bullman S. Pedamallu C.S. Sicinska E. Clancy T.E. Zhang X. Cai D. Neuberg D. Huang K. Guevara F. Nelson T. et al.Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer.Science. 2017; 358: 1443-1448Crossref PubMed Scopus (563) Google Scholar) (Figure 1D), yet it was unclear if these bacteria were active or passive participants in this process. We more recently provided an early clue as to the answer to this latter question, demonstrating that the cytokines IL-8 and CXCL1 are specifically secreted upon F. nucleatum invasion of HCT116 CRC cells and contribute to enhancing cancer cell migration directly (Casasanta et al., 2020Casasanta M.A. Yoo C.C. Udayasuryan B. Sanders B.E. Umaña A. Zhang Y. Peng H. Duncan A.J. Wang Y. Li L. et al.Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration.Sci. Signal. 2020; 13: eaba9157Crossref PubMed Google Scholar) (Figure 1E). This bacterium is able to induce alterations even at the epigenomic level, where it was discovered that F. nucleatum infection, in conjunction with Hungatella hathewayi, induces the hypermethylation of tumor suppressor gene promoters in colonic epithelial tissue (Xia et al., 2020Xia X. Wu W.K.K. Wong S.H. Liu D. Kwong T.N.Y. Nakatsu G. Yan P.S. Chuang Y.-M. Chan M.W.-Y. Coker O.O. et al.Bacteria pathogens drive host colonic epithelial cell promoter hypermethylation of tumor suppressor genes in colorectal cancer.Microbiome. 2020; 8: 108Crossref PubMed Scopus (20) Google Scholar) (Figure 1F). These observations have generated a number of fundamental questions that we believe should be a broad focus of researchers across multiple cancer types beyond the gut, including:•Are bacteria seeded early on in tumorigenesis, thereby actively contributing to tumor initiation, or do they arrive at later stages?•Are specific features of the TME favorable for bacterial localization or survival/proliferation?•How do the bacteria modify the TME?•Are there cooperative relationships among multiple bacteria types within the TME, or between tumor and bacteria?•What factors govern the bacterial interactions with tumor-associated immune cells?•Does elimination of the internalized microbes reverse their effect on the tumor?•Can microbial signatures be used to identify the type or stage of the tumor and predict therapy response and toxicity?•Why do some tumors host more diverse microbiota than others?•Can we harness the tissue or niche-specific bacterial colonization of cancers to enable targeted delivery of therapeutics? The consequences of these microbe-microbe and host-microbe interactions may materialize over long timescales. Nejman et al. suggest that there may be a low level of bacteria in every tissue and bacterial translocation increases after disruption of the epithelial barrier and increased vascular permeability (Nejman et al., 2020Nejman D. Livyatan I. Fuks G. Gavert N. Zwang Y. Geller L.T. Rotter-Maskowitz A. Weiser R. Mallel G. Gigi E. et al.The human tumor microbiome is composed of tumor type–specific intracellular bacteria.Science. 2020; 368: 973-980Crossref PubMed Scopus (404) Google Scholar). Furthermore, evidence of alterations in metabolic profiles of host cells and internalized bacteria (Kasper et al., 2020Kasper S.H. Morell-Perez C. Wyche T.P. Sana T.R. Lieberman L.A. Hett E.C. Colorectal cancer-associated anaerobic bacteria proliferate in tumor spheroids and alter the microenvironment.Sci. Rep. 2020; 10: 5321Crossref PubMed Scopus (19) Google Scholar), as well as the secretion of inflammatory cytokines, that may dramatically impact the hallmarks of cancer, raise questions on the role of secreted factors in influencing tumor progression. Answers to these questions will help identify novel therapeutic targets and reshape current cancer treatment procedures. However, many of these questions have yet to be addressed directly due to a lack of representative models to study tumor-resident bacteria. In the next section, we discuss the challenges and limitations of existing methods to study host-microbial interactions and how tissue engineering can help model the TME. To systematically interrogate host-microbe interactions, targeted questions must be defined to select appropriate experimental protocols (Fischbach, 2018Fischbach M.A. Microbiome: focus on causation and mechanism.Cell. 2018; 174: 785-790Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). Experiments in animals and humans have generally been limited to overall population/compositional studies via 16S ribosomal RNA gene sequencing and shotgun metagenomics, due to difficulties in isolation and sampling and downstream culture of bacteria (Jovel et al., 2016Jovel J. Patterson J. Wang W. Hotte N. O’Keefe S. Mitchel T. Perry T. Kao D. Mason A.L. Madsen K.L. et al.Characterization of the gut microbiome using 16S or shotgun metagenomics.Front. Microbiol. 2016; 7: 459Crossref PubMed Scopus (431) Google Scholar). Although focusing on mechanistic studies of individual microbes may appear as a low-hanging fruit, microbes exhibit contrasting behaviors when studied within a multi-species community. In fact, many metabolites are only produced in the presence of other microbes (Bertrand et al., 2014Bertrand S. Bohni N. Schnee S. Schumpp O. Gindro K. Wolfender J.-L. Metabolite induction via microorganism co-culture: a potential way to enhance chemical diversity for drug discovery.Biotechnol. Adv. 2014; 32: 1180-1204Crossref PubMed Scopus (257) Google Scholar). The secreted metabolites themselves may directly affect the tumor viability and proliferation. For example, we have previously shown that Pseudomonas aeruginosa found in breast cancer tissue secretes N-(3-oxododecanoyl)-L-homoserine lactone, which variably modulates viability of MDA-MB-231 and MCF-DCIS.com cells depending on the specific culture microenvironment (Balhouse et al., 2017Balhouse B.N. Patterson L. Schmelz E.M. Slade D.J. Verbridge S.S. N-(3-oxododecanoyl)-L-homoserine lactone interactions in the breast tumor microenvironment: implications for breast cancer viability and proliferation in vitro.PLoS One. 2017; 12: e0180372Crossref PubMed Scopus (11) Google Scholar). Paradigmatic changes in experimental and conceptual approaches are needed to develop a comprehensive understanding of all the factors that influence host-microbiome interactions in cancer. Challenges that have hindered this goal include difficulties in:•Isolating causal microorganism(s)•Preventing over-proliferation of single species in a multi-species model•Accurately replicating in vivo physiological geometry and biochemical cues•Limiting variability in organoid structures and batch-to-batch extracellular matrix (ECM) composition•Developing cell culture medium supportive of all non-microbial cells within the model•Culturing anaerobic bacteria in oxygenated models•Real-time monitoring of host and microbial cells and their associated biochemical parameters•Recapitulating in vivo microbial community composition and immune cell interactions Overcoming these bottlenecks is crucial to develop technologies to effectively dissect microbial interactions with the host and to target these therapeutically. Animal models are frequently employed due to the availability of powerful genetic tools and physiological relevance to humans. Moreover, with recent advances in whole-animal editing, animal models are becoming increasingly “humanized,” and are ideal for long-term compound studies (Hay et al., 2014Hay M. Thomas D.W. Craighead J.L. Economides C. Rosenthal J. Clinical development success rates for investigational drugs.Nat. Biotechnol. 2014; 32: 40-51Crossref PubMed Scopus (1404) Google Scholar). However, current animal models (i.e., xenograft tumor mice models) are poor representatives of human biology because they exhibit distinct bacterial compositions and immune profiles compared with humans (Mestas and Hughes, 2004Mestas J. Hughes C.C.W. Of mice and not men: differences between mouse and human immunology.J. Immunol. 2004; 172: 2731-2738Crossref PubMed Scopus (2270) Google Scholar). Furthermore, animal studies are expensive and not as scalable and accessible as other in vitro models. More specifically, when it comes to manipulating signaling molecules or growth factors, there is much less experimental control, making it challenging to add or tune elements that are necessary to mimic a physiological environment. Therefore, it is beneficial to utilize in vitro technologies that can provide valuable insights at a fraction of the cost of transgenic animals and can reduce dependence on animal experimentation at earlier screening or discovery stages of research, or to help dissect specific mechanism in later stages of study. Tissue engineering evolved as a strategy to build a tissue from the ground up and can prove to be a viable tool to reconstruct physiologically relevant in vitro models. These techniques begin from seeding cells in decellularized scaffolds, or ECM-based hydrogels. The use of stem cells and induced pluripotent stem cells (iPSCs) catapulted this field with organoid technology. Precise and tunable control with microfluidic devices and microelectromechanical systems has added further control and interrogation options to these technologies. Moreover, engineering principles guide the use of mechanical articulation to simulate biophysical cues that influence the differentiation of cells. However, a number of challenges still remain. While developing tissue engineered models, it is essential to recreate the natural homeostatic environment as well as the tumor-specific microenvironment, specifically for tumor-microbiome studies. Some challenges to this include developing the normal or physiological environment first, before incorporating the pathological tumor element. There are a host of factors within the TME that need to be considered for disease modeling. These factors markedly influence the type of microbes that colonize and infect the tumor. Figure 2 exemplifies the microenvironmental parameters to simulate the gut. There exists complex chemical, pH, nutrient, and oxygen gradients throughout the length of the gut that, for certain bacterial species, determine if the colonies are aerobic or anaerobic. The intestinal walls are composed of several different cell types including enterocytes, enteroendocrine cells, Paneth cells, goblet cells, M cells, and Tuft cells, each with unique functions. These cells help establish the epithelial barrier. The barrier itself has a high turnover rate, and any compromise to barrier may lead to microbial invasion and dissemination. Vascular and lymphatic networks skirt the walls of the intestine. In addition, cancer-associated fibroblasts, tumor-associated macrophages, stromal cells, and myriad immune cells create a highly intricate and dynamic microenvironment. Immune-host interactions are compartmentalized along the length of the intestinal tract, which additionally influences microbial diversity. A major factor to consider is mucus secreted by goblet cells, which significantly contributes to bacterial spatial aggregation (Schroeder, 2019Schroeder B.O. Fight them or feed them: how the intestinal mucus layer manages the gut microbiota.Gastroenterol. Rep. 2019; 7: 3-12Crossref PubMed Scopus (175) Google Scholar). Biomechanical cues arising from peristalsis of the gut and mucociliary flow invariably influence h" @default.
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• W3108142058 date "2020-12-01" @default.
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• W3108142058 title "Harnessing Tissue Engineering Tools to Interrogate Host-Microbiota Crosstalk in Cancer" @default.
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