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Lung cancer secreted microvesicles: underappreciated modulators of microenvironment in expanding tumors.

ABSTRACT: Microvesicles (MVs) are shed from cell membranes of several cell types and have an important function in cell-to-cell communication. Exponentially growing lung cancer cells secrete large quantities of MVs and we were interested in their role in tumor progression. We observed that both human and murine lung cancer cell lines secrete more MVs in response to non-apoptotic doses of hypoxia and irradiation. These tumor-derived (t)MVs activate and chemoattract stroma fibroblasts and endothelial cells. Furthermore, they induce expression of several pro-angiopoietic factors in stromal cells such as IL-8, VEGF, LIF, OSM, IL-11 and MMP-9. We also noticed that conditioned media harvested from stroma cells stimulated by tMVs enhanced the metastatic potential of both human and murine lung cancer cells in vivo. Thus, we postulated that tMVs are underappreciated constituents of the tumor microenvironment and play a pivotal role in tumor progression, metastasis and angiogenesis.

SUBMITTER: Wysoczynski M

PROVIDER: S-EPMC2769262 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Lung cancer secreted microvesicles: underappreciated modulators of microenvironment in expanding tumors.

Wysoczynski Marcin M Ratajczak Mariusz Z MZ

International journal of cancer 20091001 7

Microvesicles (MVs) are shed from cell membranes of several cell types and have an important function in cell-to-cell communication. Exponentially growing lung cancer cells secrete large quantities of MVs and we were interested in their role in tumor progression. We observed that both human and murine lung cancer cell lines secrete more MVs in response to non-apoptotic doses of hypoxia and irradiation. These tumor-derived (t)MVs activate and chemoattract stroma fibroblasts and endothelial cells. ...[more]

PMID: 19462451

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Project description:Epigenetic aberrations offer dynamic and reversible targets for cancer therapy; increasingly, alteration via overexpression, mutation, or rearrangement is found in genes that control the epigenome. Such alterations suggest a fundamental role in carcinogenesis. Here, we consider three epigenetic mechanisms: DNA methylation, histone tail modification and non-coding, microRNA regulation. Evidence for each of these in lung cancer origin or progression has been gathered, along with evidence that epigenetic alterations might be useful in early detection. DNA hypermethylation of tumor suppressor promoters has been observed, along with global hypomethylation and hypoacetylation, suggesting an important role for tumor suppressor gene silencing. These features have been linked as prognostic markers with poor outcome in lung cancer. Several lines of evidence have also suggested a role for miRNA in carcinogenesis and in outcome. Cigarette smoke downregulates miR-487b, which targets both RAS and MYC; RAS is also a target of miR-let-7, again downregulated in lung cancer. Together the evidence implicates epigenetic aberration in lung cancer and suggests that targeting these aberrations should be carefully explored. To date, DNA methyltransferase and histone deacetylase inhibitors have had minimal clinical activity. Explanations include the possibility that the agents are not sufficiently potent to invoke epigenetic reversion to a more normal state; that insufficient time elapses in most clinical trials to observe true epigenetic reversion; and that doses often used may provoke off-target effects such as DNA damage that prevent epigenetic reversion. Combinations of epigenetic therapies may address those problems. When epigenetic agents are used in combination with chemotherapy or targeted therapy it is hoped that downstream biological effects will provoke synergistic cytotoxicity. This review evaluates the challenges of exploiting the epigenome in the treatment of lung cancer.

Dataset Information

Lung cancer secreted microvesicles: underappreciated modulators of microenvironment in expanding tumors.

Publications

Lung cancer secreted microvesicles: underappreciated modulators of microenvironment in expanding tumors.

Similar Datasets

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