Unravelling biology and shifting paradigms in cancer with single-cell sequencing.
Baslan Timour,Hicks James
Nature reviews. Cancer
The fundamental operative unit of a cancer is the genetically and epigenetically innovative single cell. Whether proliferating or quiescent, in the primary tumour mass or disseminated elsewhere, single cells govern the parameters that dictate all facets of the biology of cancer. Thus, single-cell analyses provide the ultimate level of resolution in our quest for a fundamental understanding of this disease. Historically, this quest has been hampered by technological shortcomings. In this Opinion article, we argue that the rapidly evolving field of single-cell sequencing has unshackled the cancer research community of these shortcomings. From furthering an elemental understanding of intra-tumoural genetic heterogeneity and cancer genome evolution to illuminating the governing principles of disease relapse and metastasis, we posit that single-cell sequencing promises to unravel the biology of all facets of this disease.
10.1038/nrc.2017.58
Hallmarks of cancer: the next generation.
Hanahan Douglas,Weinberg Robert A
Cell
The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
10.1016/j.cell.2011.02.013
CCR9 and CCL25: A review of their roles in tumor promotion.
Xu Baoping,Deng Chao,Wu Xue,Ji Ting,Zhao Lin,Han Yuehu,Yang Wenwen,Qi Yating,Wang Zheng,Yang Zhi,Yang Yang
Journal of cellular physiology
Chemokines constitute a superfamily of small chemotactic cytokines with functions that are based on interactions with their corresponding receptors. It has been found that, among other functions, chemokines regulate the migratory and invasive abilities of cancer cells. Multiple studies have confirmed that chemokine receptor 9 (CCR9) and its exclusive ligand, chemokine 25 (CCL25), are overexpressed in a variety of malignant tumors and are closely associated with tumor proliferation, apoptosis, invasion, migration and drug resistance. This review evaluates recent advances in understanding the role of CCR9/CCL25 in cancer development. First, we outline the general background of chemokines in cancer and the structure and function of CCR9 and CCL25. Next, we describe the basic function of CCR9/CCL25 in the cancer process. Then, we introduce the role of CCR9/CCL25 and related signaling pathways in various cancers. Finally, future research directions are proposed. In general, this paper is intended to serve as a comprehensive repository of information on this topic and is expected to contribute to the design of other research projects and future efforts to develop treatment strategies for ameliorating the effects of CCR9/CCL25 in cancer.
10.1002/jcp.29782
Tumour dormancy in inflammatory microenvironment: A promising therapeutic strategy for cancer-related bone metastasis.
Hu Wenhui,Zhang Lincheng,Dong Yutong,Tian Zhansong,Chen Yueqi,Dong Shiwu
Cellular and molecular life sciences : CMLS
Cancer metastasis is a unique feature of malignant tumours. Even bone can become a common colonization site due to the tendency of solid tumours, including breast cancer (BCa) and prostate cancer (PCa), to metastasize to bone. Currently, a previous concept in tumour metabolism called tumour dormancy may be a promising target for antitumour treatment. When disseminated tumour cells (DTCs) metastasize to the bone microenvironment, they form a flexible regulatory network called the "bone-tumour-inflammation network". In this network, bone turnover as well as metabolism, tumour progression, angiogenesis and inflammatory responses are highly unified and coordinated, and a slight shift in this balance can result in the disruption of the microenvironment, uncontrolled inflammatory responses and excessive tumour growth. The purpose of this review is to highlight the regulatory effect of the "bone-tumour-inflammation network" in tumour dormancy. Osteoblast-secreted factors, bone turnover and macrophages are emphasized and occupy in the main part of the review. In addition, the prospective clinical application of tumour dormancy is also discussed, which shows the direction of future research.
10.1007/s00018-020-03572-1
Extracellular ATP and P2 purinergic signalling in the tumour microenvironment.
Di Virgilio Francesco,Sarti Alba Clara,Falzoni Simonetta,De Marchi Elena,Adinolfi Elena
Nature reviews. Cancer
Modulation of the biochemical composition of the tumour microenvironment is a new frontier of cancer therapy. Several immunosuppressive mechanisms operate in the milieu of most tumours, a condition that makes antitumour immunity ineffective. One of the most potent immunosuppressive factors is adenosine, which is generated in the tumour microenvironment owing to degradation of extracellular ATP. Accruing evidence over the past few years shows that ATP is one of the major biochemical constituents of the tumour microenvironment, where it acts at P2 purinergic receptors expressed on both tumour and host cells. Stimulation of P2 receptors has different effects depending on the extracellular ATP concentration, the P2 receptor subtype engaged and the target cell type. Among P2 receptors, the P2X purinergic receptor 7 (P2X7R) subtype appears to be a main player in host-tumour cell interactions. Preclinical studies in several tumour models have shown that P2X7R targeting is potentially a very effective anticancer treatment, and many pharmaceutical companies have now developed potent and selective small molecule inhibitors of P2X7R. In this Review, we report on the multiple mechanisms by which extracellular ATP shapes the tumour microenvironment and how its stimulation of host and tumour cell P2 receptors contributes to determining tumour fate.
10.1038/s41568-018-0037-0
The tumour glyco-code as a novel immune checkpoint for immunotherapy.
RodrÍguez Ernesto,Schetters Sjoerd T T,van Kooyk Yvette
Nature reviews. Immunology
Tumour growth is accompanied by tumour evasion of the immune system, a process that is facilitated by immune checkpoint molecules such as programmed cell death protein 1 (PD1). However, the role of tumour glycosylation in immune evasion has mostly been overlooked, despite the fact that aberrant tumour glycosylation alters how the immune system perceives the tumour and can also induce immunosuppressive signalling through glycan-binding receptors. As such, specific glycan signatures found on tumour cells can be considered as a novel type of immune checkpoint. In parallel, glycosylation of tumour proteins generates neo-antigens that can serve as targets for tumour-specific T cells. In this Opinion article, we highlight how the tumour 'glyco-code' modifies immunity and suggest that targeting glycans could offer new therapeutic opportunities.
10.1038/nri.2018.3
Unravelling tumour heterogeneity by single-cell profiling of circulating tumour cells.
Keller Laura,Pantel Klaus
Nature reviews. Cancer
Single-cell technologies have contributed to unravelling tumour heterogeneity, now considered a hallmark of cancer and one of the main causes of tumour resistance to cancer therapies. Liquid biopsy (LB), defined as the detection and analysis of cells or cell products released by tumours into the blood, offers an appealing minimally invasive approach that allows the characterization and monitoring of tumour heterogeneity in individual patients. Here, we will review and discuss how circulating tumour cell (CTC) analysis at single-cell resolution provides unique insights into tumour heterogeneity that are not revealed by analysis of circulating tumour DNA (ctDNA) derived from LBs. The molecular analysis of CTCs provides complementary information to that of genomic aberrations determined using ctDNA to fully describe many different cellular components (for example, DNA, RNA, proteins and metabolites) that can influence tumour heterogeneity.
10.1038/s41568-019-0180-2
Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy.
Gut
OBJECTIVE:As the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing. DESIGN:Patient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD- (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated. RESULTS:Similar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab. CONCLUSIONS:Our work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.
10.1136/gutjnl-2017-315201