Airway Microbiota as a Modulator of Lung Cancer

Recent research on cancer-associated microbial communities has elucidated the interplay between bacteria, immune cells, and tumor cells; the bacterial pathways involved in the induction of carcinogenesis; and their clinical significance. Although accumulating evidence shows that a dysbiotic condition is associated with lung carcinogenesis, the underlying mechanisms remain unclear. Microorganisms possibly trigger tumor initiation and progression, presumably via the production of bacterial toxins and other pro-inflammatory factors. The purpose of this review is to discuss the basic role of the airway microbiome in carcinogenesis and the underlying molecular mechanisms, with the aim of developing anticancer strategies involving the airway microbiota. In addition, the mechanisms via which the microbiome acts as a modulator of immunotherapies in lung cancer are summarized.

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The Role of microRNAs in the Regulation of Apoptosis in Lung Cancer and Its Application in Cancer Treatment

BioMed Research International ◽

10.1155/2014/318030 ◽

2014 ◽

Vol 2014 ◽

pp. 1-19 ◽

Cited By ~ 26

Author(s):

Norahayu Othman ◽

Noor Hasima Nagoor

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

High Frequency ◽

Tumor Suppressor Genes ◽

Molecular Mechanisms ◽

Lung Carcinogenesis ◽

The Past ◽

Late Stage Diagnosis ◽

Anticancer Treatment

Lung cancer remains to be one of the most common and serious types of cancer worldwide. While treatment is available, the survival rate of this cancer is still critically low due to late stage diagnosis and high frequency of drug resistance, thus highlighting the pressing need for a greater understanding of the molecular mechanisms involved in lung carcinogenesis. Studies in the past years have evidenced that microRNAs (miRNAs) are critical players in the regulation of various biological functions, including apoptosis, which is a process frequently evaded in cancer progression. Recently, miRNAs were demonstrated to possess proapoptotic or antiapoptotic abilities through the targeting of oncogenes or tumor suppressor genes. This review examines the involvement of miRNAs in the apoptotic process of lung cancer and will also touch on the promising evidence supporting the role of miRNAs in regulating sensitivity to anticancer treatment.

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The role of microRNA in the molecular mechanisms of resistance to EGFR tyrosine kinase inhibitor treatment in NSCLC and the current perspective on its clinical applications

Postępy Polskiej Medycyny i Farmacji ◽

10.5604/01.3001.0011.6194 ◽

2017 ◽

Vol 5 ◽

pp. 45-58

Author(s):

Adam Szpechciński ◽

Mateusz Florczuk

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Tyrosine Kinase ◽

Molecular Mechanisms ◽

Regulatory Function ◽

Cancer Tissue ◽

Lung Carcinogenesis ◽

Egfr Tyrosine Kinase ◽

Egfr Tkis

Non-small cell lung cancer (NSCLC) is the leading cause of death from cancer over the world. Currently, a large number of research studies are conducted to develop and implement new treatment strategies. Intensive efforts are also made to improve robustness of modern molecular diagnostics to identify more precisely specific genetic and epigenetic cancer features (predictive biomarkers) and adjust the most effective treatment options for individual patient (personalized therapy). So called targeted therapy based on using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is nowadays the most widely chosen form of personalized treatment in advanced NSCLC. Favorable response to treatment with EGFR TKIs depends on the presence of somatic mutations in EGFR gene, detectable in lung cancer tissue. The resistance to EGFR TKIs acquired by most patients during treatment is the main ob-stacle to overcome in NSCLC targeted therapy. miRNAs (microRNAs) are small, noncoding RNA molecules that play a keyrole in the regulation of basic cellular processes, includingdif-ferentiation, proliferation and apoptosis, by controllinggene expression at the posttranscriptional level.Deregulation of miRNA activity results in the loss of homeostasisand the development of a number of pathologies, includinglung cancer. During lung carcinogenesis, miRNAs exhibitdual regulatory function: they act as oncogenes or as tumour suppressors. Better understanding of epigenetic mechanisms re-gulating either the sensitivity or the resistance of NSCLC cells to EGFR TKIs, through activity of miRNAs, may become a breakthrough in targe-ted therapy of lung cancer. The dual regulatory role of miRNA in cancer might drive the further development of personalised therapies in NSCLC. Furthermore, stable forms of tumourrelated miRNAs are detectable in the peripheral blood of patients with NSCLC that offers the potential benefits of using extracellular miRNAs as part of the diagnostic evaluation of cancer.

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The role of exosomes in lung cancer metastasis and clinical applications: an updated review

Journal of Translational Medicine ◽

10.1186/s12967-021-02985-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lei Yin ◽

Xiaotian Liu ◽

Xuejun Shao ◽

Tao Feng ◽

Jun Xu ◽

...

Keyword(s):

Lung Cancer ◽

Drug Resistance ◽

Cancer Cell ◽

Cancer Metastasis ◽

Value Assessment ◽

Lung Carcinogenesis ◽

Research Attention ◽

Mesenchymal Transition ◽

Lung Cancer Metastasis

AbstractLung cancer is the leading cause of cancer-associated deaths accounting for 24% of all cancer deaths. As a crucial phase of tumor progression, lung cancer metastasis is linked to over 70% of these mortalities. In recent years, exosomes have received increasing research attention in their role in the induction of carcinogenesis and metastasis in the lung. In this review, recent studies on the contribution of exosomes to lung cancer metastasis are discussed, particularly highlighting the role of lung tumor-derived exosomes in immune system evasion, epithelial-mesenchymal transition, and angiogenesis, and their involvement at both the pre-metastatic and metastatic phases. The clinical application of exosomes as therapeutic drug carriers, their role in antitumor drug resistance, and their utility as predictive biomarkers in diagnosis and prognosis are also presented. The metastatic activity, a complex multistep process of cancer cell invasion, survival in blood vessels, attachment and subsequent colonization of the host's organs, is integrated with exosomal effects. Exosomes act as functional mediating factors in cell–cell communication, influencing various steps of the metastatic cascade. To this end, lung cancer cell-derived exosomes enhance cell proliferation, angiogenesis, and metastasis, regulate drug resistance, and antitumor immune activities during lung carcinogenesis, and are currently being explored as an important component in liquid biopsy assessment for diagnosing lung cancer. These nano-sized extracellular vesicles are also being explored as delivery vehicles for therapeutic molecules owing to their unique properties of biocompatibility, circulatory stability, decreased toxicity, and tumor specificity. The current knowledge of the role of exosomes highlights an array of exosome-dependent pathways and cargoes that are ripe for exploiting therapeutic targets to treat lung cancer metastasis, and for predictive value assessment in diagnosis, prognosis, and anti-tumor drug resistance.

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Microfluidic tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion

Science Advances ◽

10.1126/sciadv.abc2331 ◽

2021 ◽

Vol 7 (8) ◽

pp. eabc2331 ◽

Cited By ~ 1

Author(s):

Jose M. Ayuso ◽

Shujah Rehman ◽

Maria Virumbrales-Munoz ◽

Patrick H. McMinn ◽

Peter Geiger ◽

...

Keyword(s):

Nk Cells ◽

Immune Cells ◽

Molecular Mechanisms ◽

Nk Cell ◽

Checkpoint Inhibitors ◽

Waste Product ◽

Extended Period ◽

Cell Exhaustion

Solid tumors generate a suppressive environment that imposes an overwhelming burden on the immune system. Nutrient depletion, waste product accumulation, hypoxia, and pH acidification severely compromise the capacity of effector immune cells such as T and natural killer (NK) cells to destroy cancer cells. However, the specific molecular mechanisms driving immune suppression, as well as the capacity of immune cells to adapt to the suppressive environment, are not completely understood. Thus, here, we used an in vitro microfluidic tumor-on-a-chip platform to evaluate how NK cells respond to the tumor-induced suppressive environment. The results demonstrated that the suppressive environment created by the tumor gradually eroded NK cell cytotoxic capacity, leading to compromised NK cell surveillance and tumor tolerance. Further, NK cell exhaustion persisted for an extended period of time after removing NK cells from the microfluidic platform. Last, the addition of checkpoint inhibitors and immunomodulatory agents alleviated NK cell exhaustion.

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Role of lung and gut microbiota on lung cancer pathogenesis

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03644-0 ◽

2021 ◽

Author(s):

Yue Zhao ◽

Yuxia Liu ◽

Shuang Li ◽

Zhaoyun Peng ◽

Xiantao Liu ◽

...

Keyword(s):

Lung Cancer ◽

Gut Microbiota ◽

Cancer Progression ◽

Gut Microbiome ◽

Intestinal Flora ◽

Inflammatory Factors ◽

Cancer Pathogenesis ◽

Research Findings ◽

Relationship Of

Abstract Background Lung cancer is the leading cause of cancer-related deaths worldwide (Ferlay et al., Int J Cancer 136:E359–386, 2015). In addition, lung cancer is associated with the highest mortality among all cancer types (Wu et al., Exp Ther Med 16:3004–3010, 2018). Previous studies report that microbiota play an important role in lung cancer. Notably, changes in lung and gut microbiota, are associated with progression of lung cancer. Several studies report that lung and gut microbiome promote lung cancer initiation and development by modulating metabolic pathways, inhibiting the function of immune cells, and producing pro-inflammatory factors. In addition, some factors such as microbiota dysbiosis, affect production of bacteriotoxins, genotoxicity and virulence effect, therefore, they play a key role in cancer progression. These findings imply that lung and gut microbiome are potential markers and targets for lung cancer. However, the role of microbiota in development and progression of lung cancer has not been fully explored. Purpose The aim of this study was to systemically review recent research findings on relationship of lung and gut microbiota with lung cancer. In addition, we explored gut–lung axis and potential mechanisms of lung and gut microbiota in modulating lung cancer progression. Conclusion Pulmonary and intestinal flora influence the occurrence, development, treatment and prognosis of lung cancer, and will provide novel strategies for prevention, diagnosis, and treatment of lung cancer.

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The dynamic behavior of lipid droplets in the pre-metastatic niche

Cell Death and Disease ◽

10.1038/s41419-020-03207-0 ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Chunliang Shang ◽

Jie Qiao ◽

Hongyan Guo

Keyword(s):

Tumor Cells ◽

Immune Cells ◽

Stromal Cells ◽

Lipid Droplets ◽

Metastatic Tumor ◽

Current Evidence ◽

Biological Functions ◽

Metastatic Niche ◽

Niche Formation

AbstractThe pre-metastatic niche is a favorable microenvironment for the colonization of metastatic tumor cells in specific distant organs. Lipid droplets (LDs, also known as lipid bodies or adiposomes) have increasingly been recognized as lipid-rich, functionally dynamic organelles within tumor cells, immune cells, and other stromal cells that are linked to diverse biological functions and human diseases. Moreover, in recent years, several studies have described the indispensable role of LDs in the development of pre-metastatic niches. This review discusses current evidence related to the biogenesis, composition, and functions of LDs related to the following characteristics of the pre-metastatic niche: immunosuppression, inflammation, angiogenesis/vascular permeability, lymphangiogenesis, organotropism, reprogramming. We also address the function of LDs in mediating pre-metastatic niche formation. The potential of LDs as markers and targets for novel antimetastatic therapies will be discussed.

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Role of microRNAs in Lung Carcinogenesis Induced by Asbestos

Journal of Personalized Medicine ◽

10.3390/jpm11020097 ◽

2021 ◽

Vol 11 (2) ◽

pp. 97

Author(s):

Rakhmetkazhy Bersimbaev ◽

Olga Bulgakova ◽

Akmaral Aripova ◽

Assiya Kussainova ◽

Oralbek Ilderbayev

Keyword(s):

Lung Cancer ◽

Expression Profile ◽

Regulation Of Gene Expression ◽

International Agency ◽

Oxygen Species ◽

Lung Carcinogenesis ◽

Mrna Targets ◽

The World ◽

Post Transcriptional Regulation

MicroRNAs are a class of small noncoding endogenous RNAs 19–25 nucleotides long, which play an important role in the post-transcriptional regulation of gene expression by targeting mRNA targets with subsequent repression of translation. MicroRNAs are involved in the pathogenesis of numerous diseases, including cancer. Lung cancer is the leading cause of cancer death in the world. Lung cancer is usually associated with tobacco smoking. However, about 25% of lung cancer cases occur in people who have never smoked. According to the International Agency for Research on Cancer, asbestos has been classified as one of the cancerogenic factors for lung cancer. The mechanism of malignant transformation under the influence of asbestos is associated with the genotoxic effect of reactive oxygen species, which initiate the processes of DNA damage in the cell. However, epigenetic mechanisms such as changes in the microRNA expression profile may also be implicated in the pathogenesis of asbestos-induced lung cancer. Numerous studies have shown that microRNAs can serve as a biomarker of the effects of various adverse environmental factors on the human body. This review examines the role of microRNAs, the expression profile of which changes upon exposure to asbestos, in key processes of carcinogenesis, such as proliferation, cell survival, metastasis, neo-angiogenesis, and immune response avoidance.

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The role of FoxP3+ regulatory T cells and IDO+ immune and tumor cells in malignant melanoma – an immunohistochemical study

BMC Cancer ◽

10.1186/s12885-021-08385-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Satu Salmi ◽

Anton Lin ◽

Benjamin Hirschovits-Gerz ◽

Mari Valkonen ◽

Niina Aaltonen ◽

...

Keyword(s):

T Cells ◽

Prognostic Factors ◽

Regulatory T Cells ◽

Tumor Cells ◽

Immune Cells ◽

Positive Association ◽

Tumor Stage ◽

Melanoma Cells ◽

Melanoma Progression

Abstract Background FoxP3+ Regulatory T cells (Tregs) and indoleamine-2,3-dioxygenase (IDO) participate in the formation of an immunosuppressive tumor microenvironment (TME) in malignant cutaneous melanoma (CM). Recent studies have reported that IDO expression correlates with poor prognosis and greater Breslow’s depth, but results concerning the role of FoxP3+ Tregs in CM have been controversial. Furthermore, the correlation between IDO and Tregs has not been substantially studied in CM, although IDO is known to be an important regulator of Tregs activity. Methods We investigated the associations of FoxP3+ Tregs, IDO+ tumor cells and IDO+ stromal immune cells with tumor stage, prognostic factors and survival in CM. FoxP3 and IDO were immunohistochemically stained from 29 benign and 29 dysplastic nevi, 18 in situ -melanomas, 48 superficial and 62 deep melanomas and 67 lymph node metastases (LNMs) of CM. The number of FoxP3+ Tregs and IDO+ stromal immune cells, and the coverage and intensity of IDO+ tumor cells were analysed. Results The number of FoxP3+ Tregs and IDO+ stromal immune cells were significantly higher in malignant melanomas compared with benign lesions. The increased expression of IDO in melanoma cells was associated with poor prognostic factors, such as recurrence, nodular growth pattern and increased mitotic count. Furthermore, the expression of IDO in melanoma cells was associated with reduced recurrence˗free survival. We further showed that there was a positive correlation between IDO+ tumor cells and FoxP3+ Tregs. Conclusions These results indicate that IDO is strongly involved in melanoma progression. FoxP3+ Tregs also seems to contribute to the immunosuppressive TME in CM, but their significance in melanoma progression remains unclear. The positive association of FoxP3+ Tregs with IDO+ melanoma cells, but not with IDO+ stromal immune cells, indicates a complex interaction between IDO and Tregs in CM, which demands further studies.

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236 Evaluation of PD-L1 expression in primary lung tumor and metastatic lymph nodes in the presence of immune cells

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0236 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A253-A253

Author(s):

Chris Hansis ◽

Xiaomei Wang ◽

Tao Wang ◽

Gerald Feldman

Keyword(s):

Lung Cancer ◽

Squamous Cell Carcinoma ◽

Lymph Node ◽

Tumor Cells ◽

Squamous Cell ◽

Immune Cells ◽

Lymph Node Metastases ◽

Metastatic Lymph Node ◽

Metastatic Lymph ◽

Node Metastases

BackgroundImmunotherapies against programmed death ligand-1 (PD-L1) have been established as an effective treatment for a subset of lung cancer patients. Even though it is critical for a successful therapy to know prevalent PD-L1 expression patterns in all affected tissues, information on matching lymph node metastases and immune cells is particularly limited. The purpose of this study was thus to evaluate comparative PD-L1 expression profiles in those tissues.MethodsFDA-approved IHC assays for PD-L1 (Dako 22C3) were performed on a lung tissue array (LC814A, US Biomax) according to manufacturer’s instructions. Histopathological analysis by H-scoring was performed to determine the rate and intensity of positive tumor and immune cell staining for each of the 80 cores. The H score was calculated as follows: A total of up to 300 cells were assessed, per specimen, at 40x high-power magnification (typically over 7–10 fields). A staining level of 0–3 was then assigned to each cell, to designate the intensity of specific positive membranous-to-cytoplasmic staining. The H score was subsequently calculated as% cells staining at level 1 (x1) +% cells staining at level 2 (x2) +% cells staining at level 3 (x3) = total H score per sample. This resulted in a maximum possible H score of 300.ResultsOf the 16 adenocarcinoma tumor samples with a valid staining, 7 (44%) showed positive PD-L1 staining for tumor cells and 10 (63%) for primary immune cells. Importantly, 9 matching metastatic lymph node samples out of the 16 samples (56%) showed an increased PD-L1 H score compared to primary tumors for both tumor cells and immune cells (figure 1). Of the 15 squamous cell carcinoma samples with a valid staining, 11 (73%) showed detectable PD-L1 expression levels in the primary tumor and 12 (80%) in the primary immune cells, while 7 (47%) and 9 (60%) showed lower scores in matching metastatic lymph node tumor cells and their immune cells, respectively (figure 2). Very low or no expression of PD-L1 was detected in small cell lung cancer, as to be expected from previous studies.Abstract 236 Figure 1PD-L1 Staining in adenocarcinomaAbstract 236 Figure 2PD-L1 Staining in squamous cell carcinomaConclusionsSquamous cell carcinomas and adenocarcinomas display significant heterogeneity with regard to PD-L1 expression in associated lymph node metastases. While the reasons for this frequent discordant PD-L1 expression pattern involving both tumor and immune cells need to be investigated further, our findings may help guide the proper interpretation of PD-L1 companion diagnostic test results and subsequent therapeutic decisions.AcknowledgementsThe views in this Abstract have not been formally disseminated by the U.S. Food and Drug Administration and should not be construed to represent any agency determination or policy.

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