Unexpected guests in the tumor microenvironment:microbiome in cancer

Although intestinal microbiome have been established as an important biomarker and regulator of cancer development and therapeutic response,less is known about the role of microbiome at other body sites in cancer.Emerging evidence has revealed that the local microbiota make up an important part of the tumor microenvironment across many types of cancer,espe-cially in cancers arising from mucosal sites,including the lung,skin and gastrointestinal tract.The populations of bacteria that reside specifically within tumors have been found to be tumor-type specific,and mechanistic studies have demonstrated that tumor-associated microbiota may directly regulate cancer initiation,pro-gression and responses to chemo-or immuno-thera-pies.This review aims to provide a comprehensive review of the important literature on the microbiota in the cancerous tissue,and their function and mechanism of action in cancer development and treatment.     

The Role of Gut Microbiota in Modulating Tumor Growth and Anticancer Agent Efficacy

An increasing number of studies have revealed an interaction between gut microbiota and tumors. The enrichment of specific bacteria strains in the intestines has been found to modulate tumor growth and influence the mechanisms of tumor treatment. Various bacteria are involved in modulating the effects of chemotherapeutic drugs currently used to treat patients with cancer, and they affect not only gastrointestinal tract tumors but also distant organ tumors. In addition, changes in the gut microbiota are known to be involved in the antitumor immune response as well as the modulation of the intestinal immune system. As a result, the gut microbiota plays an important role in modulating the efficacy of immune checkpoint inhibitors. Therefore, gut microbiota could be considered as an adjuvant treatment option with other cancer treatment or as another marker for predicting treatment response. In this review, we examine how gut microbiota affects cancer treatments.     

Intratumoral bacteria are an important “accomplice” in tumor development and metastasis

As emerging tumor components, intratumoral bacteria have been found in many solid tumors. Several studies have demonstrated that different cancer subtypes have distinct microbial compositions, and mechanistic studies have shown that intratumoral bacteria may promote cancer initiation and progression through DNA damage, epigenetic modification, inflammatory responses, modulation of host immunity and activation of oncogenes or oncogenic pathways. Moreover, intratumoral bacteria have been shown to modulate tumor metastasis and chemotherapy response. A better understanding of the tumor microenvironment and its associated microbiota will facilitate the design of new metabolically engineered species, opening up a new era of intratumoral bacteria-based cancer therapy. However, many questions remain to be resolved, such as where intratumoral bacteria originate and whether there is a direct causal relationship between intratumoral bacteria and tumor susceptibility. In addition, suitable preclinical models and more advanced detection techniques are crucial for studying the biological functions of intratumoral bacteria. In this review, we summarize the complicated role of intratumoral bacteria in the regulation of cancer development and metastasis and discuss their carcinogenic mechanisms and potential therapeutic aspects.     

Microenvironment and tumors—a nurturing relationship

When exposed to adverse environmental conditions, cells degrade their own content to recycle cellular building blocks through a process called autophagy. A large body of literature has connected autophagy to cancer, but most studies up until now focused on its function in transformed cells. In her thesis, Nadja Katheder dissected the role of autophagy in a well-characterized neoplastic in vivo tumor model in Drosophila and demonstrates a novel non-cell-autonomous requirement of this process for tumor growth. Neighboring epithelial cells and distal tissues increase autophagy in the presence of a malignant tumor. Pharmacological autophagy inhibition reduces tumor growth and genetic ablation of autophagy in the microenvironment reveals a tumor-supportive role of this process in this specific cell population. Tumor cells are metabolically stressed and induce autophagy in their neighbors through a TNFα-JNK-IL-6 signaling cascade. Moreover, they are dependent on amino acid import to sustain their proliferation, which indicates a coupling of metabolism between these two cell populations. Finally, allografted growth-impaired tumors from autophagy-deficient donor animals resume growth in an autophagy-competent host. Together, the results described in this thesis highlight the tumor-promoting role of autophagy the microenvironment and show that cancer cells engage their epithelial neighbors as essential contributors aiding their own growth.     

The microbiota and aging microenvironment in pancreatic cancer: Cell origin and fate

Cellular senescence is a state of growth arrest where nonproliferative cells accumulate over time in the aging microenvironment under multiple external factors. Senescent cells exert a double-edged sword effect in an autocrine or paracrine manner: physiologically, they contribute to tissue development, prevent the multiplication of damaged cells and contribute to tissue repair and tumor suppression while favoring the onset of age-related diseases, including tumors. The microbiota in human tissues is intricately linked to cellular senescence and is reportedly present in the tissues of various tumors (including pancreatic tumors), closely associated with tumorigenesis and progression. The microbiota can induce cells to undergo senescence, and their long-term effects can assist senescent cells in transforming and successfully escaping senescence, contributing to tumorigenesis and progression. Here, we focus on the correlation between the microbiota, cellular senescence, and pancreatic cancer to provide novel ideas for the study and therapy of pancreatic cancer.     

The Role of Respiratory Microbiota in Lung Cancer

Recently, the impact of microorganisms on tumor growth and metastasis has attracted great attention. The pathogenesis and progression of lung cancer are related to an increase in respiratory bacterial load as well as changes in the bacterial community because the microbiota affects tumors in many ways, including canceration, metastasis, angiogenesis, and treatment. The microbiota may increase tumor susceptibility by altering metabolism and immune responses, promoting inflammation, and increasing toxic effects. The microbiota can regulate tumor metastasis by altering multiple cell signaling pathways and participate in tumor angiogenesis through vascular endothelial growth factors (VEGF), endothelial cells (ECs), inflammatory factors and inflammatory cells. Tumor angiogenesis not only maintains tumor growth at the primary site but also promotes tumor metastasis and invasion. Therefore, angiogenesis is an important mediator of the interaction between microorganisms and tumors. The microbiota also plays a part in antitumor therapy. Alteration of the microbiota caused by antibiotics can regulate tumor growth and metastasis. Moreover, the microbiota also influences the efficacy and toxicity of tumor immunotherapy and chemotherapy. Finally, the effects of air pollution, a risk factor for lung cancer, on microorganisms and the possible role of respiratory microorganisms in the effects of air pollution on lung cancer are discussed.     

胃癌的肿瘤微环境研究进展

肿瘤微环境是决定肿瘤细胞行为的主要影响因素,有别于正常细胞与其周围组织所形成的微环境,组织缺氧和酸中毒、间质高压形成、大量生长因子和蛋白水解酶的产生及免疫炎性反应等构成了肿瘤组织代谢环境的生物学特征,这种特性在肿瘤的发生、进展、转移中扮演重要的角色。胃癌早期症状不典型、转移迅速、死亡率高,是消化系统最常见的恶性肿瘤,目前,关于肿瘤微环境的研究尚处于起步阶段,对胃癌肿瘤微环境的研究有助于我们进一步认识胃癌发生发展的机制,并为临床诊断、治疗胃癌提供依据。因此,本文就近年来在胃癌肿瘤微环境方面的研究进展作一综述。     

Gut microbiota alterations are distinct for primary colorectal cancer and hepatocellular carcinoma

Colorectal cancer(CRC)and hepatocellular carcinoma(HCC)are the second and third most common causes of death by cancer,respectively.The etiologies of the two cancers are either infectious insult or due to chronic use of alcohol,smoking,diet,obesity and diabetes.Patho-logical changes in the composition of the gut microbiota that lead to intestinal inflammation are a common factor for both HCC and CRC.However,the gut microbiota of the cancer patient evolves with disease pathogenesis in unique ways that are affected by etiologies and envi-ronmental factors.in this review,we examine the chan-ges that occur in the composition of the gut microbiota across the stages of the HCC and CRC.Based on the idea that the gut microblota are an additional"lifeline"and contribute to the tumor microenvironment,we can observe from previously published literature how the microbiota can cause a shift in the balance from normal→ inflammation → diminished inflammation from early to later disease stages.This pattern leads to the hypothesis that tumor survival depends on a less pro-inflammatory tumor microenvironment.The differences observed in the gut microbiota composition between different disease etiologies as well as between HCC and CRC suggest that the tumor microenvironment is unique for each case.     

Role of cancer-associated fibroblasts in breast cancer development and prognosis

Since Paget's "Seed and Soil" hypothesis in 1889 on cancer growth and metastasis, several studies on various solid tumors have confirmed the active role of the tumor milieu on the onset, growth and spread of neoplastic cells. Fibroblasts constitute the major components of the tumor microenvironment (stroma), and are therefore the most studied cell type. Therefore, a large amount of data has emerged showing the cancer-promoting function of these cells through paracrine effects that escort tumor cells through all the carcinogenesis steps. This involves many signaling proteins that transmit the message in both directions, allowing cooperative crosstalk between cancer cells and their stroma. This prompted several researchers to investigate the potential use of the molecular and cellular features of active stromal fibroblasts to generate specific tools for prevention, prognosis and treatment of cancer. Herein, I review the cellular and molecular features of active cancer-associated fibroblasts and their origin. Additionally, I summarize our current understanding of the procarcinogenic actions of these cells and their potential prognostic value for breast cancer patients.     

Gut microbiome in cancer immunotherapy: Current trends,translational challenges and future possibilities

Gut microbiota is regarded as a crucial regulator of the immune system. Healthy gut microbiota plays a specialized role in host xenobiotics, nutrition, drug metabolism, regulation of the structural integrity of the gut mucosal barrier, defense against infections, and immunomodulation. It is now understood that any imbalance in gut microbiota composition from that present in a healthy state is linked to genetic susceptibility to a number of metabolic disorders, including diabetes, autoimmunity, and cancer. Recent research has suggested that immunotherapy can treat many different cancer types with fewer side effects and better ability to eradicate tumors than conventional chemotherapy or radiotherapy. However, a significant number of patients eventually develop immunotherapy resistance. A strong correlation was observed between the composition of the gut microbiome and the effectiveness of treatment by examining the variations between populations that responded to immunotherapy and those that did not. Therefore, we suggest that modulating the microbiome could be a potential adjuvant therapy for cancer immunotherapy and that the architecture of the gut microbiota may be helpful in explaining the variation in treatment response. Herein, we focus on recent research on the interactions among the gut microbiome, host immunity, and cancer immunotherapy. In addition, we highlighted the clinical manifestations, future opportunities, and limitations of microbiome manipulation in cancer immunotherapy.     

Direct in vivo evidence for tumor propagation by glioblastoma cancer stem cells

High-grade gliomas (World Health Organization grade III anaplastic astrocytoma and grade IV glioblastoma multiforme), the most prevalent primary malignant brain tumors, display a cellular hierarchy with self-renewing, tumorigenic cancer stem cells (CSCs) at the apex. While the CSC hypothesis has been an attractive model to describe many aspects of tumor behavior, it remains controversial due to unresolved issues including the use of ex vivo analyses with differential growth conditions. A CSC population has been confirmed in malignant gliomas by preferential tumor formation from cells directly isolated from patient biopsy specimens. However, direct comparison of multiple tumor cell populations with analysis of the resulting phenotypes of each population within a representative tumor environment has not been clearly described. To directly test the relative tumorigenic potential of CSCs and non-stem tumor cells in the same microenvironment, we interrogated matched tumor populations purified from a primary human tumor transplanted into a xenograft mouse model and monitored competitive in vivo tumor growth studies using serial in vivo intravital microscopy. While CSCs were a small minority of the initial transplanted cancer cell population, the CSCs, not the non-stem tumor cells, drove tumor formation and yielded tumors displaying a cellular hierarchy. In the resulting tumors, a fraction of the initial transplanted CSCs maintained expression of stem cell and proliferation markers, which were significantly higher compared to the non-stem tumor cell population and demonstrated that CSCs generated cellular heterogeneity within the tumor. These head-to-head comparisons between matched CSCs and non-stem tumor cells provide the first functional evidence using live imaging that in the same microenvironment, CSCs more than non-stem tumor cells are responsible for tumor propagation, confirming the functional definition of a CSC.     

TREM-1 Is Induced in Tumor Associated Macrophages by Cyclo-Oxygenase Pathway in Human Non-Small Cell Lung Cancer

It is increasingly recognized that the tumor microenvironment plays a critical role in the initiation and progression of lung cancer. In particular interaction of cancer cells, macrophages, and inflammatory response in the tumor microenvironment has been shown to facilitate cancer cell invasion and metastasis. The specific molecular pathways in macrophages that immunoedit tumor growth are not well defined. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a member of the super immunoglobulin family expressed on a select group of myeloid cells mainly monocyte/macrophages. Recent studies suggest that expression of TREM-1 in tumors may predict cancer aggressiveness and disease outcomes in liver and lung cancer however the mechanism of TREM-1 expression in the setting of cancer is not defined. In this study we demonstrate that tumor tissue from patients with non-small cell lung cancer show an increased expression of TREM-1 and PGE₂. Immunohistochemistry and immunofluorescence confirmed that the expression of TREM-1 was selectively seen in CD68 positive macrophages. By employing an in vitro model we confirmed that expression of TREM-1 is increased in macrophages that are co-cultured with human lung cancer cells. Studies with COX-2 inhibitors and siCOX-2 showed that expression of TREM-1 in macrophages in tumor microenvironment is dependent on COX-2 signaling. These studies for the first time define a link between tumor COX-2 induction, PGE₂ production and expression of TREM-1 in macrophages in tumor microenvironment and suggest that TREM-1 might be a novel target for tumor immunomodulation.     

Impact of tumor microenvironment on oncolytic viral therapy

Interactions between tumor cells and their microenvironment have been shown to play a very significant role in the initiation, progression, and invasiveness of cancer. These tumor–stromal interactions are capable of altering the delivery and effectiveness of therapeutics into the tumor and are also known to influence future resistance and re-growth after treatment. Here we review recent advances in the understanding of the tumor microenvironment and its response to oncolytic viral therapy. The multifaceted environmental response to viral therapy can influence viral infection, replication, and propagation within the tumor. Recent studies have unveiled the complicated temporal changes in the tumor vasculature post-oncolytic virus (OV) treatment, and their impact on tumor biology. Similarly, the secreted extracellular matrix in solid tumors can affect both infection and spread of the therapeutic virus. Together, these complex changes in the tumor microenvironment also modulate the activation of the innate antiviral host immune response, leading to quick and efficient viral clearance. In order to combat these detrimental responses, viruses have been combined with pharmacological adjuvants and “armed” with therapeutic genes in order to suppress the pernicious environmental conditions following therapy. In this review we will discuss the impact of the tumor environment on viral therapy and examine some of the recent literature investigating methods of modulating this environment to enhance oncolysis.     

Priming cancer cells for drug resistance: role of the fibroblast niche

Conventional and targeted chemotherapies remain integral strategies to treat solid tumors. Despite the large number of anti-cancer drugs available, chemotherapy does not completely eradicate disease. Disease recurrence and the growth of drug resistant tumors remain significant problems in anti-cancer treatment. To develop more effective treatment strategies, it is important to understand the underlying cellular and molecular mechanisms of drug resistance. It is generally accepted that cancer cells do not function alone, but evolve through interactions with the surrounding tumor microenvironment. As key cellular components of the tumor microenvironment, fibroblasts regulate the growth and progression of many solid tumors. Emerging studies demonstrate that fibroblasts secrete a multitude of factors that enable cancer cells to become drug resistant. This review will explore how fibroblast secretion of soluble factors act on cancer cells to enhance cancer cell survival and cancer stem cell renewal, contributing to the development of drug resistant cancer.     

Effect of P2X purinergic receptors in tumor progression and as a potential target for anti-tumor therapy

The development of tumors is a complex pathological process involving multiple factors, multiple steps, and multiple genes. Their prevention and treatment have always been a difficult problem at present. A large number of studies have proved that the tumor microenvironment plays an important role in the progression of tumors. The tumor microenvironment is the place where tumor cells depend for survival, and it plays an important role in regulating the growth, proliferation, apoptosis, migration, and invasion of tumor cells. P2X purinergic receptors, which depend on the ATP ion channel, can be activated by ATP in the tumor microenvironment, and by mediating tumor cells and related cells (such as immune cells) in the tumor microenvironment. They play an important regulatory role on the effects of the skeleton, membrane fluidity, and intracellular molecular metabolism of tumor cells. Therefore, here, we outlined the biological characteristics of P2X purinergic receptors, described the effect of tumor microenvironment on tumor progression, and discussed the effect of ATP on tumor. Moreover, we explored the role of P2X purinergic receptors in the development of tumors and anti-tumor therapy. These data indicate that P2X purinergic receptors may be used as another potential pharmacological target for tumor prevention and treatment.

     

Mast cells in tumor growth: Angiogenesis,tissue remodelling and immune-modulation

There is a growing acceptance that tumor-infiltrating myeloid cells play an active role in tumor growth and mast cells are one of the earliest cell types to infiltrate developing tumors. Mast cells accumulate at the boundary between healthy tissues and malignancies and are often found in close association with blood vessels within the tumor microenvironment. They express many pro-angiogenic compounds, and may play an early role in angiogenesis within developing tumors. Mast cells also remodel extracellular matrix during wound healing, and this function is subverted in tumor growth, promoting tumor spread and metastasis. In addition, mast cells modulate immune responses by dampening immune rejection or directing immune cell recruitment, depending on local stimuli. In this review, we focus on key roles for mast cells in angiogenesis, tissue remodelling and immune modulation and highlight recent findings on the integral role that mast cells play in tumor growth. New findings suggest that mast cells may serve as a novel therapeutic target for cancer treatment and that inhibiting mast cell function may lead to tumor regression.     

MicroRNA regulation in cancer-associated fibroblasts

The microenvironment of cancer cells has proven to be a critical component of tumors that strongly influences cancer development and progression into invasive and metastatic disease. Compared to normal tissue, dramatic differences in gene expression occur in multiple cell types that constitute the tumor microenvironment including cancer-associated fibroblasts (CAFs) that are important stromal components of growing tumors. In this review, we present recent advances in understanding how microRNAs are deregulated in cancer-associated fibroblasts (CAFs) and how this affects tumor biology. The microRNA signature of CAFs is discussed with respect to their functional relevance to tumor cells as well as other cell types involved in tumor homeostasis.     

Elimination of breast tumor-associated chondroitin sulfate promotes metastasis

Breast cancer is one of the leading causes of cancer-related deaths amongst women in the USA. The tumor microenvironment has been suggested to be an attractive therapeutic target for treatment of cancers. The glycosaminoglycan chondroitin sulfate, as part of the cellular microenvironment, consists of long linear chains of repeating disaccharide units, which are covalently attached to core proteins to form chondroitin sulfate-proteoglycans. In vitro studies have implicated chondroitin sulfate in various aspects of carcinogenesis, whereas the in vivo roles of chondroitin sulfate are less clear. Drastically elevated levels of chondroitin sulfate have been observed within the stromal compartment of many solid tumors, including human breast carcinomas, the significance of which is unknown. We examined the role of tumor-associated chondroitin sulfate in breast cancer progression. Enzymatic elimination of endogenous chondroitin sulfate by intra-tumor injections of chondroitinase ABC leads to the development of secondary tumors and increased lung metastases, while primary orthotopic tumor growth was not affected. These results establish a metastasis-inhibiting effect of primary breast tumor-associated chondroitin sulfate, which may open novel carbohydrate-based therapeutic strategies to combat breast cancer.     

Emerging advances in engineered macrophages for tumor immunotherapy

Macrophages are versatile antigen-presenting cells. Recent studies suggest that engineered modifications of macrophages may confer better tumor therapy. Genetic engineering of macrophages with specific chimeric antigen receptors offers new possibilities for treatment of solid tumors and has received significant attention. In vitro gene editing of macrophages and infusion into the body can inhibit the immunosuppressive effect of the tumor microenvironment in solid tumors. This strategy is flexible and can be applied to all stages of cancer treatment. In contrast, nongenetic engineering tools are used to block relevant signaling pathways in immunosuppressive responses. In addition, macrophages can be loaded with drugs and engineered into cellular drug delivery systems. Here, we analyze the effect of the chimeric antigen receptor platform on macrophages and other existing engineering modifications of macrophages, highlighting their status, challenges and future perspectives. Indeed, our analyses show that new approaches in the treatment of solid tumors will likely exploit macrophages, an innate immune cell.