A Macrophage Gene Expression Signature Defines a Field Effect in the Lung Tumor Microenvironment

Stearman, Robert S.; Dwyer‐Nield, Lori D.; Grady, Michael C.; Malkinson, Alvin M.; Geraci, Mark W.

doi:10.1158/0008-5472.can-07-0988

Cited by 40 publications

(36 citation statements)

References 47 publications

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“…The tobacco smoking-induced changes in gene expression and cellular functions are not confined to the pulmonary airway epithelium but have also been reported in the nasal and buccal epithelium (38,39), alveolar macrophages (40,41), and peripheral blood (42). These findings are consistent with the previously presented hypotheses regarding the systemic inflammatory process operative in patients with COPD as well as in those with lung cancer.…”

Section: The Field Cancerization Effectsupporting

confidence: 89%

Smoking and Lung Cancer: The Role of Inflammation

Walser

Cui²,

Yanagawa³

et al. 2008

Proceedings of the American Thoracic Society

275

158

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Worldwide over 1 million people die due to lung cancer each year. It is estimated that cigarette smoking explains almost 90% of lung cancer risk in men and 70 to 80% in women. Clinically evident lung cancers have multiple genetic and epigenetic abnormalities. These abnormalities may result in activation of oncogenes and inactivation of tumor-suppressor genes. Chronic inflammation, which is known to promote cancer, may result both from smoking and from genetic abnormalities. These mediators in turn may be responsible for increased macrophage recruitment, delayed neutrophil clearance, and increase in reactive oxygen species (ROS). Thus, the pulmonary environment presents a unique milieu in which lung carcinogenesis proceeds in complicity with the host cellular network. The pulmonary diseases that are associated with the greatest risk for lung cancer are characterized by abundant and deregulated inflammation. Pulmonary disorders such as chronic obstructive pulmonary disease (COPD)/emphysema are characterized by profound abnormalities in inflammatory and fibrotic pathways. The cytokines and growth factors aberrantly produced in COPD and the developing tumor microenvironment have been found to have deleterious properties that simultaneously pave the way for both epithelialmesenchymal transition (EMT) and destruction of specific host cellmediated immune responses. Full definition of these pathways will afford the opportunity to intervene in specific inflammatory events mediating lung tumorigenesis and resistance to therapy.

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Section: The Field Cancerization Effectsupporting

confidence: 89%

Smoking and Lung Cancer: The Role of Inflammation

Walser

Cui²,

Yanagawa³

et al. 2008

Proceedings of the American Thoracic Society

275

158

View full text Add to dashboard Cite

show abstract

“…Likewise, host cells in microenvironment may induce genetic changes and clonal selection in tumor cells that generates a subpopulation of tumor cells with the capability to invade into the surrounding tissue. 25,26 Many recent studies support the first hypothesis; for example, Stearman et al 27 reported that macrophages in lung tumor environment displayed a unique gene expression signature suggesting a role in promoting tumor metastasis. Richardson et al 28 conducted experiments to compare expression profiles in the 4 major components of microenvironment: tumor epithelium, tumor associated stroma, normal epithelium and normal stroma using human prostate cancer specimens.…”

Section: Discussionmentioning

confidence: 87%

The invasive potential of human melanoma cell lines correlates with their ability to alter fibroblast gene expression in vitro and the stromal microenvironment in vivo

Dragulev

Zigrino

et al. 2009

Intl Journal of Cancer

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The tumor microenvironment is thought to play an important role in invasion and metastasis. Previously, we have shown that signaling from melanoma cells can alter the gene expression profiles of fibroblasts in vitro and in vivo. To investigate whether the capacity to signal fibroblasts and alter host gene expression profiles is correlated to the invasive potential of specific human melanoma cell lines, we assayed changes in gene expression of fibroblasts when cocultured with the human melanoma cell lines BLM, MV3, A2058, SK-mel28 and WM164. Results indicated that the gene expression of key chemokines and cytokines, such as IL-1B, IL-8, IL-6 and CCL2/MCP1, was significantly upregulated in fibroblasts cocultured with the invasive melanoma lines BLM and MV3 compared to fibroblasts cocultured with noninvasive WM164 cells. The results were verified by quantitative RT-PCR as well as by protein assay and supported by immunohistochemistry of human invasive melanoma. Furthermore, a role for fibroblast-secreted IL-1B in the invasion of melanoma was demonstrated in vitro, where siRNA silencing of IL-1B in melanoma-stimulated fibroblasts resulted in a diminution of melanoma invasion. Although CCL2/MCP1, a chemoattractant for macrophages, was shown to be upregulated in fibroblasts cocultured with metastatic melanoma cell lines, immunohistochemical analysis of human melanoma also indicated CCL2/MCP1 production associated with the melanoma. In summary, these experiments indicate that the invasiveness of melanoma can partly be correlated to its ability to stimulate host stromal fibroblasts to give rise to the secretion of chemokines that generate a microenvironment that is conductive for melanoma invasion and metastasis. ' UICCKey words: melanoma; stroma; metastasis; IL-1B; invasion; gene expression; microenvironmentThe capacity for invasion and metastasis is one of the hallmarks of tumor malignancy. The role of host-tumor communication and the tumor microenvironment in tumor cell invasion and metastasis has been recognized as being critical in this process. 1 The complex interaction between invasive tumor cells, stromal cells, lymphocytes and extracellular matrix as represented by the invasive tumor microenvironment is only beginning to be understood. Further investigation in tumor microenvironments will generate new possibilities in terms of identifying key mechanisms of tumor cell invasion and metastasis and potentially therapeutic nodes for attenuating primary tumor metastasis. 2,3 Fibroblasts comprise one of the principal cell types of the stromal compartment, and recent studies have demonstrated that stromal fibroblasts are important in tumor cell migration through the stroma.4,5 Stimulation of resident stromal fibroblasts by the presence of invasive tumor cells gives rise to alterations in the gene and protein expression patterns of these cells, which have been interpreted as proinvasive and prometastatic.6 Upregulation of key chemokine and cytokine expression in stromal fibroblasts in the presence of migrating human m...

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“…We found that MMP19 gene expression is modestly increased compared with histologically normal tissue adjacent to the tumor. So-called "field effects," the concept that suggests that cells in proximity to cancer cells are premalignant and should exhibit at least some, but not all, of the genetic alterations that are present in the fully developed cancer (49)(50)(51)(52), may explain the only modest differences in MMP19 expression between tumor and adjacent "normal" tissue. Further study is necessary to elucidate extracellular cues that may lead to increased expression of MMP19.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-19 Promotes Metastatic BehaviorIn Vitroand Is Associated with Increased Mortality in Non–Small Cell Lung Cancer

Herazo-Maya

Nukui

et al. 2014

Am J Respir Crit Care Med

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Rationale: Lung cancer is the leading cause of cancer death in both men and women in the United States and worldwide. Matrix metalloproteinases (MMPs) have been implicated in the development and progression of lung cancer, but their role in the molecular pathogenesis of lung cancer remains unclear. We have found that MMP19, a relatively novel member of the MMP family, is overexpressed in lung tumors when compared with control subjects.Objectives: To test the hypothesis that MMP19 plays a significant role in the development and progression of non-small cell lung cancer (NSCLC).Methods: We have analyzed lung cancer gene expression data, immunostained lung tumors for MMP19, and performed in vitro assays to test the effects of MMP19 in NSCLC cells. Measurements and Main Results:We found that MMP19 gene and protein expression is increased in lung cancer tumors compared with adjacent and histologically normal lung tissues. In three independent datasets, increased MMP19 gene expression conferred a poorer prognosis in NSCLC. In vitro, we found that overexpression of MMP19 promotes epithelial-mesenchymal transition, migration, and invasiveness in multiple NSCLC cell lines. Overexpression of MMP19 with a mutation at the catalytic site did not impair epithelial-mesenchymal transition or expression of prometastasis genes. We also found that miR-30 isoforms, a microRNA family predicted to target MMP19, is markedly downregulated in human lung cancer and regulates MMP19 expression.Conclusions: Taken together, these findings suggest that MMP19 is associated with the development and progression of NSCLC and may be a potential biomarker of disease severity and outcome.

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A Macrophage Gene Expression Signature Defines a Field Effect in the Lung Tumor Microenvironment

Cited by 40 publications

References 47 publications

Smoking and Lung Cancer: The Role of Inflammation

Smoking and Lung Cancer: The Role of Inflammation

The invasive potential of human melanoma cell lines correlates with their ability to alter fibroblast gene expression in vitro and the stromal microenvironment in vivo

Matrix Metalloproteinase-19 Promotes Metastatic BehaviorIn Vitroand Is Associated with Increased Mortality in Non–Small Cell Lung Cancer

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