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L. Roz
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MA17 - Genetic Drivers (ID 409)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Satouchi, G.R. Simon
- Coordinates: 12/07/2016, 14:20 - 15:50, Lehar 1-2
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MA17.09 - Premature Fibroblast Senescence in Large Cell Carcinoma Provides Enhanced Growth and Invasive Advantages to Cancer Cells in Culture and in vivo (ID 5352)
15:20 - 15:26 | Author(s): L. Roz
- Abstract
- Presentation
Background:
Tumor-associated fibroblasts (TAFs) are increasingly regarded as essential co-conspirators for tumor progression in all solid tumors including non-small cell lung cancer. While most TAFs exhibit activation markers indicative of a myofibroblast-like phenotype, senescence markers have been reported in a growing list of selected cancer types only. However, the presence of senescent TAFs in lung cancer remains undefined. Assessing senescence in lung TAFs is important because previous studies have reported that senescent TAFs enhances tumor growth, which is in marked contrast with the widely accepted tumor-suppressive role of senescence in cancer cells.
Methods:
We examined common senescence markers in patient derived lung TAFs from the 3 major non-small cell lung cancer (NSCLC) subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Given the difficulties in gathering LCC-TAFs owing to the lower prevalence of LCC compared to the other subtypes, primary fibroblasts from 2 independent fibroblast collections were used. Senescence markers included senescence-associated beta-galactosidase, permanent growth arrest and spreading.
Results:
We found an enrichment of the myofibroblast-like phenotype in TAFs regardless their histologic subtype, yet senescence was observed in LCC-TAFs only regardless their neuroendocrine status. Likewise, co-culturing normal lung fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to induce senescence, and this induction was prevented in the presence of an antioxidant, indicating that it is mediated through oxidative stress. Remarkably, senescent fibroblasts provided growth and invasive advantages to LCC cells in culture and in vivo beyond those effects provided by control (non-senescent) fibroblasts.
Conclusion:
Our findings expand recent evidence that challenges the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless their histologic subtype. Of note, because LCC often distinguishes itself in the clinic by its aggressive nature, our findings support that senescent or senescent-like TAFs may contribute to the selective aggressive behavior of LCC tumors.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-017 - Circulating miRNAs in Lung Cancer Are Associated to Pro-Tumorigenic and Immunosuppressive Microenvironment (ID 5449)
14:30 - 14:30 | Author(s): L. Roz
- Abstract
Background:
We previously reported the identification of diagnostic miRNA signatures in plasma samples of lung cancer patients detected by low dose computed tomography (LDCT) screening. Circulating miRNAs are released into the bloodstream by different mechanisms such as passive leakage from damaged cells or active secretion through extracellular-vesicles or protein complexes
Methods:
To evaluate the potential origin and the release of the 24 miRNAs of the diagnostic signature we analyzed their expression by real-time or digital PCR in both cells and conditioned medium (CM) from cancer cell and different cell types of the lung microenvironment. Lung tissues and cell-blocks were analyzed by miRNAs in situ hybridization (ISH). Modulation of miRNAs after in vitro treatments known to induce changes associated with cancer progression, in different cell types was assessed and correlated to changes observed in circulating miRNAs signatures.
Results:
24-miRNAs analysis showed higher abundance in specific cellular components such as mir-145 in fibroblasts, mir-126 in endothelial cells, mir-133a in skeletal muscle cells or mir-451 and 142-3p in hematopoietic cells. Generally, tumor cells showed lower levels of miRNAs compared to bronchial epithelial cells. MiRNAs specific localization in lung tissue was confirmed by ISH. We observed that mir-451 is specifically expressed in lung interstitial alveolar walls while mir-126 by endothelial cells outside the tumor bulk; miR-145 is characteristic of fibroblast and muscle cells and miR-142-3p of hematopoietic cells, fibroblast and muscle whereas mir-21 is over-expressed in the tumor. The analysis of miRNAs in CM showed that miRNAs secretion is correlated with cellular expression for most cell types (Pearson correlation range: 0.41-0.80). Interestingly, platelets and granulocytes were the components that mostly secreted miRNAs. In vitro experiments showed that endothelial cells under hypoxic condition up-regulate mir-126 and that mir-145 was up-regulated and secreted in lung cancer-associated compared to normal fibroblasts. Interestingly, during conversion of T lymphocytes into T regulatory cells up-regulation of mir-15b, mir-19b and mir-320 was observed whereas mir-15b and mir-197 were up-regulated in the conversion of macrophages into M2 phenotype. Modulation of miRNAs in immune and stromal cells was consistent with up-regulation of the same miRNAs observed in plasma samples.
Conclusion:
Our findings on the origin of circulating miRNAs support the conclusion that plasma miRNAs are heterogeneous and secreted by different cellular components of lung microenvironment rather than by tumor cells. In particular, we demonstrated that a pro-tumorigenic and immunosuppressive microenvironment contributes to the de-regulation of miRNAs observed in plasma of lung cancer patients.
