Probing the tumor micro(b)environment

doi:10.1126/science.abc1464

GSTDTAP > 气候变化

DOI	10.1126/science.abc1464
	Probing the tumor micro(b)environment
	Chloe E. Atreya; Peter J. Turnbaugh
	2020-05-29
发表期刊	Science
出版年	2020
英文摘要	Bacteria have been implicated in the initiation and progression of cancers originating on mucosal surfaces that either harbor a diverse microbial community (microbiota) or are routinely exposed to microbes from the environment ([ 1 ][1]–[ 3 ][2]). Far less is known about the potential for bacteria to influence tumors in body sites that are typically considered sterile. One hypothesis is that the abundant and diverse microbiotas found on mucosal surfaces may exert “remote control” by releasing small molecules into circulation ([ 4 ][3], [ 5 ][4]). An alternative, nonconflicting hypothesis is that the tumor microenvironment harbors microbes that exert local effects. This hypothesis is supported by the detection of bacteria in a growing number of tumor types ([ 6 ][5], [ 7 ][6]), although the reliability of distinguishing low-abundance bacteria from contamination has been questioned ([ 8 ][7]). On page 973 of this issue, Nejman et al. ([ 9 ][8]) present the most rigorous and comprehensive survey of bacteria in human tumor samples to date. Nejman et al. use a new five-region 16S ribosomal RNA gene sequencing method, microscopy, and cell culture to characterize tumor-residing bacteria at known and previously uncharacterized sites. They report that most cancers harbor bacteria, albeit at low diversity except in breast cancer. Surprisingly, these bacteria appear to be intracellular within both cancer and immune cells. Moreover, they report associations between specific bacteria and tumor type and subtype, smoking status, and immunotherapy response. These results raise multiple important questions for future study (see the figure). For example, is the level of diversity and physiological status of these bacterial cells sufficient to constitute a “microbiota”? Although the defining characteristics of microbiotas remain in flux, two general themes are extensive microbe-microbe and host-microbe interactions, often over long time scales. Are the tumor-residing bacteria found within human cells able to communicate with each other? Prior work ([ 6 ][5]) suggests that bacteria found in tumors can metabolize drugs; however, the overall viability and metabolic activity of tumor-residing bacteria are unclear. ![Figure][9] The hidden microbiota inside cancer Intratumoral bacteria have been detected in both mucosal (exposed) body sites and protected sites. Nejman et al. examined bacterial occurrence in multiple primary tumor sites (black dots) and found that tumor cells and immune cells may harbor lipopolysaccharide-expressing (LPS+) bacteria, whereas macrophages contain at least remnants of LPS+ and lipoteichoic acid–expressing (LTA+) bacteria. These findings raise numerous questions that require further study. GRAPHIC: KELLIE HOLOSKI/ SCIENCE The stability of bacterial diversity in tumors remains to be determined. Are tumor-residing bacteria seeded early on in tumorigenesis, or does the tumor alter the microenvironment such that bacteria can continually invade? In mouse models of pancreatic cancer ([ 7 ][6]), the gut microbiota appears to determine which bacteria are found in tumors, suggesting that there is a potential for bacteria to migrate into tumors at later stages. Longitudinal studies in patients with paired analyses of microbial diversity in tumors and mucosal surfaces are an important next step. Why are bacteria found in tumors? One possibility raised by Nejman et al. is that there are always low amounts of bacteria in human tissue, which is supported by analyses of matched normal adjacent tissue from the mammary glands of patients and even healthy controls ([ 9 ][8]). In precancerous conditions, the detection of enterotoxigenic bacteria may portend a generalized procarcinogenic inflammatory state ([ 10 ][10]). After tumorigenesis, disruptions to physical and molecular barriers, together with relative immunosuppression, may increase the potential for bacterial translocation to sites that are normally sterile. This “leakiness” of the tumor microenvironment has been extensively described in the context of vascular permeability; however, the degree to which leakiness enables bacterial invasiveness remains unclear. Additionally, the observation that tumor-associated bacteria are intracellular raises the possibility that the bacteria do not actually move freely into tumors or adjacent tissues—they may be transported there, intact or in fragments, through the migration of immune or cancerous cells. A key barrier to progress is the lack of representative models for studying tumor-residing bacteria or other low-biomass microbial communities ([ 8 ][7]). Studies of colorectal cancer demonstrate the persistence of viable Fusobacterium over successive passages of human tumors in immunodeficient mice ([ 11 ][11]). However, laboratory mice harbor microbial communities ([ 12 ][12]) and immune profiles that are distinct from those found in humans. Development of “triple-humanized” models wherein cancer, immune, and microbial cells are transplanted from patients into germ-free mice may be necessary. These models could help to untangle the relationships between tumor-residing bacteria and treatment response. By contrast, there is abundant evidence that gut bacteria modulate the immunotherapy responsiveness of cancers, even at distant sites ([ 4 ][3]). Immune cells in the tumor microenvironment also play major and actionable roles, but does this extend to tumor-associated microbes? For a given cancer type, it will be important to determine the contribution of microbial composition relative to other tumor cell intrinsic and extrinsic factors that drive malignancy. The conceptual shift toward studying bacteria within tumors provides challenges and opportunities for translational research. Unlike the microbiotas found on mucosal surfaces, tumor-residing bacteria are not readily manipulatable. Current options for microbiota modulation rely on dietary, pharmaceutical, and microbiological perturbations ([ 13 ][13]). It remains unknown if tumor-residing bacteria depend at all on dietary substrates or if they subsist entirely on host-derived nutrients. Targeting intracellular tumor-residing bacteria also poses drug-delivery challenges; it may be possible to co-opt antibody-drug conjugates or other methods to specifically target bacteria. Although there is a long history of delivering viable bacteria to tumors ([ 14 ][14]), the risks and benefits of this approach need to be carefully considered. Nejman et al. emphasize that diverse bacteria are found on and in the human body. Continued investigation may benefit from the rich history of research on intracellular bacteria in insects and plants. Intracellular bacterial pathogens harbor elaborate machinery to manipulate host cellular pathways ([ 15 ][15]); it will be interesting to see if tumor-residing bacteria encode similar effectors that enable their survival and dissemination. Achieving a comprehensive understanding of the tumor microenvironment is a daunting yet critical step toward an organism-wide mechanistic model of cancer progression and, if successful, may unlock the next wave of precision cancer diagnostics and therapeutics. 1. [↵][16]1. D. Börnigen et al ., Sci. Rep. 7, 17686 (2017). [OpenUrl][17] 2. 1. A. D. Kostic et al ., Genome Res. 22, 292 (2012). 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/271744
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Chloe E. Atreya,Peter J. Turnbaugh. Probing the tumor micro(b)environment[J]. Science,2020.
APA	Chloe E. Atreya,&Peter J. Turnbaugh.(2020).Probing the tumor micro(b)environment.Science.
MLA	Chloe E. Atreya,et al."Probing the tumor micro(b)environment".Science (2020).