Abstract
Matrix metalloproteinase 10 (MMP-10; stromelysin 2) is a member of a large family of structurally related matrix metalloproteinases, many of which have been implicated in tumor progression, invasion and metastasis. We recently identified Mmp10 as a gene that is highly induced in tumor-initiating lung bronchioalveolar stem cells (BASCs) upon activation of oncogenic Kras in a mouse model of lung adenocarcinoma. However, the potential role of Mmp10 in lung tumorigenesis has not been addressed. Here, we demonstrate that Mmp10 is overexpressed in lung tumors induced by either the smoke carcinogen urethane or oncogenic Kras. In addition, we report a significant reduction in lung tumor number and size after urethane exposure or genetic activation of oncogenic Kras in Mmp10 null (Mmp10−/−) mice. This inhibitory effect is reflected in a defect in the ability of Mmp10-deficient BASCs to expand and undergo transformation in response to urethane or oncogenic Kras in vivo and in vitro, demonstrating a role for Mmp10 in the tumor-initiating activity of Kras-transformed lung stem cells. To determine the potential relevance of MMP10 in human cancer we analyzed Mmp10 expression in publicly-available gene expression profiles of human cancers. Our analysis reveals that MMP10 is highly overexpressed in human lung tumors. Gene set enhancement analysis (GSEA) demonstrates that elevated MMP10 expression correlates with both cancer stem cell and tumor metastasis genomic signatures in human lung cancer. Finally, Mmp10 is elevated in many human tumor types suggesting a widespread role for Mmp10 in human malignancy. We conclude that Mmp10 plays an important role in lung tumor initiation via maintenance of a highly tumorigenic, cancer-initiating, stem-like cell population, and that Mmp10 expression is associated with stem-like, highly metastatic genotypes in human lung cancers. These results indicate that Mmp10 may represent a novel therapeutic approach to target lung cancer stem cells.
Highlights
Non-small cell lung cancer (NSCLC) is the most common cause of cancer death in the United States [1]
Mmp10 loss inhibits Kras-mediated lung tumorigenesis In order to determine whether Mmp10 is involved in lung tumor formation, mice were treated with the smoke carcinogen urethane to induce lung adenocarcinoma tumors using well-established protocols [23]
Analysis of tumor grade using the system described by KellySpratt et al [26] demonstrated that urethane-induced tumors from Ntg and Mmp102/2 mice showed a similar distribution of tumors along the hyperplasia-adenoma-carcinoma progression scheme (Figure 1E)
Summary
Non-small cell lung cancer (NSCLC) is the most common cause of cancer death in the United States [1]. Emerging evidence supports the existence of rare subpopulations of cancer cells with stem-like characteristics [2,3,4]. These cancer-initiating cells or cancer stem cells (CSCs) exhibit selfrenewal, tumor-initiating activity, and the ability to support tumor maintenance and metastasis [2,4,5,6]. CSCs exhibit intrinsic resistance to chemotherapy [7,8], underlining the need to identify new therapeutic targets to effectively eradicate CSCs. CSCs share molecular and genomic features with embryonic stem cells, and embryonic stem cell genomic signatures are enriched in highly tumorigenic cancer stem cells. Such CSCs have been described in leukemia [9], and solid tumors, including melanoma [10], breast [11], brain [12,13,14], prostate [15], head and neck [16], pancreatic [17], colon carcinomas [18,19], and lung [20,21]
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