Regulation of invadopodia by the tumor microenvironment

The tumor microenvironment consists of stromal cells, extracellular matrix (ECM), and signaling molecules that communicate with cancer cells. As tumors grow and develop, the tumor microenvironment changes. In addition, the tumor microenvironment is not only influenced by signals from tumor cells, but also stromal components contribute to tumor progression and metastasis by affecting cancer cell function. One of the mechanisms that cancer cells use to invade and metastasize is mediated by actin-rich, proteolytic structures called invadopodia. Here, we discuss how signals from the tumor environment, including growth factors, hypoxia, pH, metabolism, and stromal cell interactions, affect the formation and function of invadopodia to regulate cancer cell invasion and metastasis. Understanding how the tumor microenvironment affects invadopodia biology could aid in the development of effective therapeutics to target cancer cell invasion and metastasis.     

肿瘤细胞和骨微环境在骨转移中的作用

随着肿瘤治疗水平的提高,肿瘤患者的生存期显著延长,转移性骨肿瘤的发生率呈增长趋势.骨转移引起的剧烈的临床症状和其较长的潜伏期,以及缺乏有效的治疗方法,极大降低了患者的生活质量.本文主要综述了骨转移相关的细胞特征及骨微环境在骨转移中的作用,并分析了影响骨转移形成的相关分子因素,为骨转移的定向分子治疗提供进一步的理论依据.     

Tumor immune microenvironment: sanctuary of tumor and target for immunotherapy

The tumor immune microenvironment (TIME) is the cellular environment in which tumors exist. This includes: surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, lymphocytes, signaling molecules, immune checkpoint proteins and the extracellular matrix (ECM). The TIME plays a critical role in cancer progression and regulation. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells. The molecules and cells in the TIME influence disease outcome by altering the balance of suppressive versus cytotoxic responses in the vicinity of the tumor. Having a better understanding of the tumor immune microenvironment will pave the way for identifying new targets for immunotherapies that promote cancer elimination.     

microRNAs在肿瘤免疫中的调控作用

microRNAs（miRNAs）是一类转录后调控基因表达的内源性非编码微小RNA。愈来愈多的研究显示,miRNAs在肿瘤免疫应答中发挥重要调控作用。一方面,miRNAs通过转录后调控ICAM（intercellular adhesion molecule）、B7（CD80／86）和HLA—G（human leucocyte antigen—G）等肿瘤表面分子的表达,影响肿瘤的免疫原性;另一方面,miRNAs通过平衡肿瘤局部的细胞因子微环境或调控肿瘤免疫相关细胞的分化、发育及功能发挥,调节机体抗肿瘤免疫应答。为后续深入研究肿瘤与宿主的相互作用机制,以及发展更有效的肿瘤生物治疗手段,就目前miRNAs在肿瘤免疫中的调控作用的研究进展做一综述。     

p53 in cell invasion,podosomes, and invadopodia

Cell invasion of the extracellular matrix is prerequisite to cross tissue migration of tumor cells in cancer metastasis, and vascular smooth muscle cells in atherosclerosis. The tumor suppressor p53, better known for its roles in the regulation of cell cycle and apoptosis, has ignited much interest in its function as a suppressor of cell migration and invasion. How p53 and its gain-of-function mutants regulate cell invasion remains a puzzle and a challenge for future studies. In recent years, podosomes and invadopodia have also gained center stage status as veritable apparatus specialized in cell invasion. It is not clear, however, whether p53 regulates cell invasion through podosomes and invadopodia. In this review, evidence supporting a negative role of p53 in podosomes formation in vascular smooth muscle cells will be surveyed, and signaling nodes that may mediate this regulation in other cell types will be explored.     

The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis

Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy.     

Metabolic regulation of ferroptosis in the tumor microenvironment

Ferroptosis is an iron-dependent, nonapoptotic form of regulated cell death triggered by impaired redox and antioxidant machinery and propagated by the accumulation of toxic lipid peroxides. A compendium of experimental studies suggests that ferroptosis is tumor-suppressive. Sensitivity or resistance to ferroptosis can be regulated by cell-autonomous and non-cell-autonomous metabolic mechanisms. This includes a role for ferroptosis that extends beyond the tumor cells themselves, mediated by components of the tumor microenvironment, including T cells and other immune cells. Herein, we review the intrinsic and extrinsic factors that promote the sensitivity of cancer cells to ferroptosis and conclude by describing approaches to harness the full utility of ferroptotic agents as therapeutic options for cancer therapy.     

溶瘤病毒调控肿瘤微环境及联合治疗的研究进展

溶瘤病毒是一类天然的或经改造后获得具有靶向杀伤癌细胞能力的病毒,除了能特异性杀伤肿瘤细胞外,经改造后的溶瘤病毒对肿瘤微环境的调控作用也会影响其最终疗效.通过调控肿瘤微环境中肿瘤细胞抗原的表达、免疫抑制状态、肿瘤相关成纤维细胞及肿瘤血管新生等,溶瘤病毒为肿瘤的治疗提供了更为系统的治疗策略;联合免疫检查点抑制剂的使用能使两者获得协同和互补的功效,进一步提升了肿瘤全面和有效的治疗.本文将对溶瘤病毒对肿瘤微环境调控作用及联合治疗的研究进展进行综述.     

p53 in cell invasion,podosomes, and invadopodia

Cell invasion of the extracellular matrix is prerequisite to cross tissue migration of tumor cells in cancer metastasis, and vascular smooth muscle cells in atherosclerosis. The tumor suppressor p53, better known for its roles in the regulation of cell cycle and apoptosis, has ignited much interest in its function as a suppressor of cell migration and invasion. How p53 and its gain-of-function mutants regulate cell invasion remains a puzzle and a challenge for future studies. In recent years, podosomes and invadopodia have also gained center stage status as veritable apparatus specialized in cell invasion. It is not clear, however, whether p53 regulates cell invasion through podosomes and invadopodia. In this review, evidence supporting a negative role of p53 in podosomes formation in vascular smooth muscle cells will be surveyed, and signaling nodes that may mediate this regulation in other cell types will be explored.     

In situ antitumor vaccination: Targeting the tumor microenvironment

Tumor microenvironment is known to play important roles in tumor progression. Many therapies, targeting the tumor microenvironment, are designed and applied in the clinic. One of these approaches is in situ antitumor therapy. This way, bacteria, antibodies, plasmid DNA, viruses, and cells are intratumorally delivered into the tumor site as “in-situ antitumor vaccine,” which seeks to enhance immunogenicity and generate systemic T cell responses. In addition, this intratumoral therapy can alter the tumor microenvironment from immunosuppressive to immunostimulatory while limiting the risk of systemic exposure and associated toxicity. Contemporarily, promising preclinical results and some initial success in clinical trials have been obtained after intratumoral therapy.     

The hypoxic microenvironment: A determinant of cancer stem cell evolution

Tumors are often viewed as unique entities with specific behaviors. However, tumors are a mixture of differentially evolved subpopulations of cells in constant Darwinian evolution, selecting the fittest clone and allowing it to outgrow the rest. As in the natural environment, the niche defines the properties the fittest clones must possess. Therefore, there can be multiple fit clones because of the various microenvironments inside a single tumor. Hypoxia is considered to be a major feature of the tumor microenvironment and is a potential contributor to the cancer stem cell (CSC) phenotype and its enhanced tumorigenicity. The acidic microenvironment around hypoxic cells is accompanied by the activation of a subset of proteases that contribute to metastasis. Because of aberrant angiogenesis and the inaccessibility of their locations, hypoxic cells are less likely to accumulate therapeutic concentrations of chemotherapeutics that can lead to therapeutic resistance. Therefore, the targeting of the hypoxic CSC niche in combination with chemotherapy may provide a promising strategy for eradicating CSCs. In this review, we examine the cancer stem cell hypothesis and its relationship to the microenvironment, specifically to hypoxia and the subsequent metabolic switch and how they shape tumor behavior.     

Motility cues in the tumor microenvironment

It is now increasingly recognized that the microenvironment plays a critical role in the progression of tumors. Perhaps less obvious is the concept that the microenvironment may share responsibility in determining the "malignant" traits of tumor cells, i.e. invasiveness and metastasis. If tumors are tissues, however unbalanced, rather than a collection of "malignant" cells recruiting local resources for the purpose of growth, then it is inevitable that tumor cells will respond to local stimuli. These stimuli include cues for motility and migration, which normally appear in tissues undergoing formation, remodeling or healing. Carcinoma cells are likely to be sensitive to the motility cues that normally regulate epithelial morphogenetic movements such as ingression, delamination, invagination, and tube or sheet migration. "Malignant" tumors, then, can be redefined as those in which these cues arise more frequently or act more effectively. Here, we expand on this view and propose that invasion and metastasis may be the outcome of tumor cell responses to microenvironmental motility cues. Understanding how such motility cues arise and act, both in normal and tumor tissue, should be a high priority in cancer research.     

Spatial transcriptomics and proteomics technologies for deconvoluting the tumor microenvironment

The tumor microenvironment (TME) harbors heterogeneous contents and plays critical roles in tumorigenesis, metastasis, and drug resistance. Therefore, the deconvolution of the TME becomes increasingly essential to every aspect of cancer research and treatment. Novel spatially-resolved high-plex molecular profiling technologies have been emerging rapidly as powerful tools to obtain in-depth understanding from TME perspectives due to their capacity to allow high-plex protein and RNA profiling while keeping valuable spatial information. Based on our practical experience, we review a variety of available spatial proteogenomic technologies, including 10X Visium, GeoMx Digital Spatial Profiler (DSP), cyclic immunofluorescence-based CODEX and Multi-Omyx, mass spectrometry (MS)-based imaging mass spectrometry (IMS) and multiplex ion-beam imaging (MIBI). We also discuss FISSEQ, MERFISH, Slide-seq, and HDST, some of which may become commercially available in the near future. In particular, with our experience, we elaborate on DSP for spatial proteogenomic profiling and discuss its unique features designed for immuno-oncology and propose anticipation towards its future direction. The emerging spatially technologies are rapidly reshaping the magnitude of our understanding of the TME.     

Identification immunophenotyping of lung adenocarcinomas based on the tumor microenvironment

The tumor immune microenvironment is heterogeneous, and its impact on treatment responses is not well understood. It is still a challenge to analyze the interaction between malignant cells and the tumor microenvironment to apply suitable immunotherapy in lung adenocarcinoma. We performed the nonnegative matrix factorization method to 513 messenger RNA expression profiles of lung adenocarcinomas (LUADs) from The Cancer Genome Atlas (TCGA) to obtain an immune-related expression pattern. Subsequently, we characterized the immune-related gene signatures and clinical and survival characteristics. We used 576 patients from Gene Expression Omnibus to confirm our findings. Of the patients in the training cohort, 51% had a high immune enrichment score, high expression of immune cell signaling, cytolytic activity, and interferon (IFN)-related signatures (all P < .05). We denoted these as the Immune Class. We further subdivided the Immune Class into two subclasses based on the tumor microenvironment. These were denoted the Active Immune Class and Exhausted Immune Class. The former showed significant IFN, T-cells, M1 macrophage signatures, and better prognosis (all P < .05), while the latter presented an exhausted immune response with activated stromal enrichment, M2 macrophage signatures, and immunosuppressive factors such as WNT/transforming growth factor-β (all P < .05). Furthermore, we predicted the response of our immunophenotypes to immunological checkpoint inhibitors (P < .05). Our findings provide a novel insight into the immune-related state of LUAD and can identify the patients who will be receptive to suitable immunotherapeutic treatments.     

Effect of mesenchymal stem cells-derived exosomes on tumor microenvironment: Tumor progression versus tumor suppression

Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into different cell types. Owing to their immunosuppressive and anti-inflammatory properties, they are widely used in regenerative medicine, but they have a dual effect on cancer progression and exert both growth-stimulatory or -inhibitory effects on different cancer types. It has been proposed that these controversial effects of MSC in tumor microenvironment (TME) are mediated by their polarization to proinflammatory or anti-inflammatory phenotype. In addition, they can polarize the immune system cells that in turn influence tumor progression. One of the mechanisms involved in the TME communications is extracellular vesicles (EVs). MSCs, as one of cell populations in TME, produce a large amount of EVs that can influence tumor development. Similar to MSC, MSC-EVs can exert both anti- or protumorigenic effects. In the current study, we will investigate the current knowledge related to MSC role in cancer progression with a focus on the MSC-EV content in limiting tumor growth, angiogenesis, and metastasis. We suppose MSC-EVs can be used as safe vehicles for delivering antitumor agents to TME.     

Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment

Every year about 500,000 people in the United States die as a result of cancer. Among them, 90% exhibit systemic disease with metastasis. Considering this high rate of incidence and mortality, it is critical to understand the mechanisms behind metastasis and identify new targets for therapy. In recent years, two broad mechanisms for metastasis have received significant attention: epithelial-to-mesenchymal transition (EMT) and tumor microenvironment interactions. EMT is believed to be a major mechanism by which cancer cells become migratory and invasive. Various cancer cells--both in vivo and in vitro--demonstrate features of epithelial-to-mesenchymal-like transition. In addition, many steps of metastasis are influenced by host contributions from the tumor microenvironment, which help determine the course and severity of metastasis. Here we evaluate the diverse mechanisms of EMT and tumor microenvironment interactions in the progression of cancer, and construct a rational argument for targeting these pathways to control metastasis.     

Reshaping of the tumor microenvironment by cellular senescence: An opportunity for senotherapies

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