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Progression and metastasis of lung cancer.

ABSTRACT: Metastasis in lung cancer is a multifaceted process. In this review, we will dissect the process in several isolated steps such as angiogenesis, hypoxia, circulation, and establishment of a metastatic focus. In reality, several of these processes overlap and occur even simultaneously, but such a presentation would be unreadable. Metastasis requires cell migration toward higher oxygen tension, which is based on changing the structure of the cell (epithelial-mesenchymal transition), orientation within the stroma and stroma interaction, and communication with the immune system to avoid attack. Once in the blood stream, cells have to survive trapping by the coagulation system, to survive shear stress in small blood vessels, and to find the right location for extravasation. Once outside in the metastatic locus, tumor cells have to learn the communication with the "foreign" stroma cells to establish vascular supply and again express molecules, which induce immune tolerance.

SUBMITTER: Popper HH

PROVIDER: S-EPMC4821869 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Progression and metastasis of lung cancer.

Popper Helmut H HH

Cancer metastasis reviews 20160301 1

Metastasis in lung cancer is a multifaceted process. In this review, we will dissect the process in several isolated steps such as angiogenesis, hypoxia, circulation, and establishment of a metastatic focus. In reality, several of these processes overlap and occur even simultaneously, but such a presentation would be unreadable. Metastasis requires cell migration toward higher oxygen tension, which is based on changing the structure of the cell (epithelial-mesenchymal transition), orientation wi ...[more]

PMID: 27018053

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Project description:BackgroundLung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide. Moreover, it is highly susceptible to distant metastasis, which is the main cause of pain in advanced lung cancer, and frequently occurs in the bone. This study aimed to identify the differentially expressed genes (DEGs) related to metastatic bone disease in lung cancer using bioinformatics methods and to analyze the risk factors influencing the incidence of secondary bone metastasis in lung cancer.MethodsGene expression profiles from the GSE175601 and GSE10799 datasets in the Gene Expression Omnibus (GEO) database were analyzed to screen for the DEGs associated with lung cancer bone metastasis. The STRING database was used to construct a protein-protein interaction (PPI) network, and the MCODE plugin was used to identify the key genes. The expression of these important genes in lung tumor tissues and their correlation with prognosis were validated in The Cancer Genome Atlas (TCGA) database. An examination of clinical data from patients diagnosed with stage IV lung adenocarcinoma treated at the Anhui No. 2 Provincial People's Hospital was conducted. Immunohistochemistry was used to examine the expression of key genes in lung cancer tumor tissues. A binary logistic regression analysis was conducted to examine the interactions in the expression of critical genes associated with bone metastasis in lung carcinoma patients.ResultsIn total, 59 DEGs were identified in the GSE175601 and GSE10799 datasets through Venn diagram construction. The PPI network analysis revealed two significant modules and eight candidate genes (LAPTM5, LCP2, CD53, ARHGAP25, C1QA, DES, MYH11, and VIM). According to TCGA database analysis, in carcinogenic tissues of the lung, the expression of these eight critical genes is downregulated. Further, only the lung cancer patients who had high expressions of ARHGAP25 had an improved progress-free interval (PFI) (P<0.05), disease-specific survival (DSS), and overall survival (OS). Of the 49 with stage IV lung adenocarcinoma patients included in the study, 27 (55.10%) developed bone metastasis. The immunohistochemical (IHC) results indicated that the expression score of ARHGAP25 was significantly lower in the group with bone metastasis (3.93±2.95) than the group without bone metastasis (6.64±3.62) (P=0.006). The proportion of patients with low ARHGAP25 expression was significantly higher in the group with bone metastasis (70.37%, 19/27) than the group without bone metastasis (31.82%, 7/22) (P=0.007). The binary logistic regression analysis identified serum alkaline phosphatase (ALP) and ARHGAP25 expression levels as independent risk factors for the occurrence of secondary bone metastatic disease in lung carcinoma patients.ConclusionsThe key gene ARHGAP25 identified through bioinformatics for lung cancer bone metastasis was significantly downregulated. Its low expression constitutes an independent risk factor for secondary bone metastatic disease in patients with lung carcinoma.

Project description:BackgroundAccumulating evidence suggests that M2-polarized tumor-associated macrophages (TAMs) play an important role in cancer progression and metastasis, making M2 polarization of TAMs an ever more appealing target for therapeutic intervention. Astragaloside IV (AS-IV), a saponin component isolated from Astragali radix, has been reported to inhibit the invasion and metastasis of lung cancer, but its effects on TAMs during lung cancer progression have not been investigated.MethodsHuman THP-1 monocytes were induced to differentiate into M2 macrophages through treatments with IL-4, IL-13, and phorbol myristate acetate (PMA). We used the lung cancer cell lines A549 and H1299 cultured in conditioned medium from M2 macrophages (M2-CM) to investigate the effects of AS-IV on tumor growth, invasion, migration, and angiogenesis of lung cancer cells. Macrophage subset distribution, M1 and M2 macrophage-associated markers, and mRNA expression were analyzed by flow cytometry and quantitative PCR. The activation of adenosine monophosphate-activated protein kinase (AMPK) signaling pathways that mediate M2-CM-promoted tumor migration was detected using western blotting.ResultsHere we found that AS-IV significantly inhibited IL-13 and IL-4-induced M2 polarization of macrophages, as illustrated by reduced expression of CD206 and M2-associated genes, and that AS-IV suppressed the M2-CM-induced invasion, migration, and angiogenesis of A549 and H1299 cells. In vivo experiments demonstrated that AS-IV greatly inhibited tumor growth and reduced the number of metastases of Lewis lung cancer. The percentage of M2 macrophages was decreased in tumor tissue after AS-IV treatment. Furthermore, AS-IV inhibited AMPKα activation in M2 macrophages, and silencing of AMPKα partially abrogated the inhibitory effect of AS-IV.ConclusionsAS-IV reduced the growth, invasion, migration, and angiogenesis of lung cancer by blocking the M2 polarization of macrophages partially through the AMPK signaling pathway, which appears to play an important role in AS-IV's ability to inhibit the metastasis of lung cancer.

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Progression and metastasis of lung cancer.

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Progression and metastasis of lung cancer.

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