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L. Ampollini
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ORAL 07 - Lung Cancer Pathogenesis (ID 91)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:J. Sage, E. Brambilla
- Coordinates: 9/07/2015, 10:45 - 12:15, 102+104+106
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ORAL07.05 - Differential Tumorigenic Properties of Mesenchymal Cells From Neoplastic and Non-Neoplastic Human Lung in NSCLC (ID 1006)
11:28 - 11:39 | Author(s): L. Ampollini
- Abstract
- Presentation
Background:
Cancer Initiating Cells (CICs) and their niches may open new avenues in the pathogenesis and management of lung cancer. A relevant component of the niche is represented by supportive stromal cells that control the fate of CICs by a reciprocal cross-talk. The understanding of these cellular events could represent a significant advancement in cancer biology and treatment. Recent observations by our and other laboratories have suggested that mesenchymal stromal cells (MSC) regulate lung cancer growth and resistance, thus generating large expectations in novel anti-cancer strategies. The aim of our study was to determine whether MSC isolated from NSCLC and from non-neoplastic human lung samples possess different biologic properties and tumorigenic potential.
Methods:
Fresh samples of neoplastic and spared lungs from 58 male patients (80% smokers) affected by primary pulmonary adenocarcinoma undergoing surgical resection were processed. Stromal cells were separated from epithelial cells by negative selection using EpCAM (CD326)-based immunomagnetic sorting. After further enrichment, we could expand for at least 14 passages a population of CD90, CD105, CD73 and CD44 positive MSC from lung cancer (Lc-MSC) and non-neoplastic (Nn-MSC) lung tissue. The oncogenic potential of these cells from the same patient was tested on a Calu-3-based in vitro model of NSCLC by co-culture and conditioned media (CM) and in vivo by xenotransplantation in Balb/c Nude mice. In vivo cell tracking was achieved by pre-labeling MSC with Quantum dots 585 (Qdots). Morphometric assessment of tissue composition and immunofluorescence combined with FISH analysis of human X and Y chromosomes was performed on xenografted tumors.
Results:
Nearly 30x10[6] cells could be typically obtained after 3 passages in each case, however, compared to Nn-MSC, cultures of Lc-MSC displayed lower growth kinetic and mitotic index while higher survival and HIF-1-alpha (Hypoxia-inducible-factor-1) upregulation in response to hypoxia was observed. A larger fraction of Lc-MSC expressed transcription factors involved in stemness (Oct3/4, SOX2) and in bronchioalveolar (TTF1, ETS-1, CCL10) commitment. Co-cultures demonstrated that Lc-MSC significantly increased Calu-3 growth as compared to Nn-MSC in transwell assay and by contact. CM from Lc-MSC similarly promoted Calu-3 expansion as compared to Nn-MSC. When 2.5x10[6] Lc-MSC or Nn-MSC from the same patient were subcutaneously co-injected with Calu-3, a 38% and 17% increase in tumor volume was respectively observed, compared to the injection of an equal number of Calu-3 alone (CTRL). Lc-MSC or Nn-MSC injected alone did not generate tumors. Quantitative estimation of the in vivo expansion of neoplastic cells indicated that the addition of Lc-MSC increased by 6-fold and 29-fold Calu-3 replication compared to Nn-MSC and CTRL, respectively. Cell tracking documented that Qdots labelled MSC were located at the boundary of neoplastic epithelial glands generated by X-chromosome polysomic Calu-3 cells. A comparative molecular analysis of Lc-MSC and Nn-MSC is ongoing for the identification of distinctive signalling pathways implicated in the microenvironemental control of CIC on NSCLC development.
Conclusion:
Profound differences exist in the biology and oncogenic potential of intratumoral and normal lung MSC strongly supporting the notion that the tumor microenvironment may represent a potential target of new customized therapeutic strategies.
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-017 - microRNAs Expression in Malignant Pleural Mesothelioma, Asbestosis and Benign Pulmonary Disease (ID 2663)
09:30 - 09:30 | Author(s): L. Ampollini
- Abstract
Background:
To evaluate the diagnostic potential of a panel of microRNAs in plasma samples of patients with malignant pleural mesothelioma (MPM).
Methods:
A group of patients with pathological diagnosis of MPM were randomly selected from a prospective mesothelioma database. Similarly, a group of patients with asbestosis and one with benign pulmonary disease, were chosen for comparison. A panel of miRNA including miR-16, miR-17, miR-21, miR-126 and miR-486 were evaluated. VEGF (vascular endothelial growth factor) was evaluated in plasma samples of patients with mesothelioma. Analysis of covariance (ANCOVA) followed by Bonferroni post-hoc test were used for multiple comparisons. P<0.05 was considered significant.
Results:
14 patients with malignant pleural mesothelioma, 14 patients with asbestosis and 21 patients with benign pulmonary disease were studied. The expression of miR-16 (p=0.018), miR-17 (p=0.024) and miR-126 (p=0.019) was significantly lower in patients with MPM compared with patients with benign pulmonary disease. Interestingly, miR-486 was able to discriminate patients with MPM compared to patients with asbestosis (p=0.004). Considering patients with MPM, miR-17 (p=0.023) and miR-486 (p=0.015) were significantly more expressed in patients with epithelial type than in patients with sarcomatoid and biphasic type. Moreover, the expression of miR-16 (p<0.0001), miR-17 (p<0.0001), miR-21 (p=0.004), miR-126 (p=0.0016) and miR-486 (p=0.003) was significantly lower in patients with asbestosis compared with subjects with benign pulmonary disease. In MPM plasma samples, VEGF expression was negatively correlated to miR-126 (p=0.004).
Conclusion:
The expression of miR-16, miR-17 and miR-126 was able to distinguish patients with MPM compared with patients with benign pulmonary diseases. miR-17 and miR-486 were significantly higher in patients with epithelial mesothelioma. An immunohistochemistry analysis evaluating the expression of VEGF in MPM tissue samples is ongoing. The available data support the role of miRNAs in the aetiology of MPM, suggesting their possible use as diagnostic markers of the disease.
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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-036 - Primary Pulmonary Large Cell Carcinoma with Syncytiotrophoblastic Aspect: Report of a Case (ID 2751)
09:30 - 09:30 | Author(s): L. Ampollini
- Abstract
Background:
To present the case of a primary large cell lung carcinoma with syncytiotrophoblastic aspect.
Methods:
A 54-year-old smoking man (60 pack/years), with no significant past medical history, presented for incidental radiological finding of a 5cm mass in the right middle lobe with partial invasion of the lower lobe (Fig.1). A PET/CT-scan showed a unique intense FDG-uptake of the pulmonary mass. A trans-thoracic fine-needle aspiration led to the diagnosis of non-small-cell lung cancer with sarcomatoid features. Preoperative cardiac and pulmonary function tests were normal. Figure 1
Results:
The patient underwent a right middle lobectomy and wedge resection of the lower lobe and radical lymphadenectomy through a posterolateral thoracotomy. The postoperative course was uneventful; the patient was discharged on the seventh postoperative day. After 52 months the patient is alive and disease-free. Macroscopically, the mass measured 5.5cm, had a greyish colour with lobulated margins. Microscopically, a poor differentiated tumor characterized by giant and medium pleomorphic cells sometimes with syncytial-trophoblastic features were observed (Fig.2a). Immunohistochemically, tumor cells were positive for beta-human-chorionic-gonadotrophin (Beta-HCG) (Fig.2b), anti-endomisium antibody (EMA), placental alkaline phosphatase (PLAP) e cytokeratin 7 (CK 7); the cells resulted negative for octamer-binding transcription factor-4 (OCT-4) (Fig.2c), spalt like transcription factor 4 (SALL4) (Fig.2d) and glypican-3. A subsequent genital examination and testicular ultrasonography excluded the presence of a primary gonadal choriocarcinoma. Beta-HCG serum levels were undetectable after surgery. Based on the above findings, a diagnosis of primary large cell lung carcinoma with syncytiotrophoblastic aspect was made. Final pathological stage was pT2aN0M0. No adjuvant therapy was proposed.Figure 1
Conclusion:
Large cell lung carcinoma with syncytiotrophoblastic aspect is an extremely rare finding. The prognosis is usually poor irrespective of the treatment; a few long-term survivors have been reported.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-114 - IASLC and WHO 2004 Grading System as Prognostic Factors in 492 Cases of Pulmonary Adenocarcinoma (ID 2647)
09:30 - 09:30 | Author(s): L. Ampollini
- Abstract
Background:
Primary aim of the study was to evaluate the prognostic value of the IASLC grading system and the WHO 2004 classification on a consecutive series of resected primary pulmonary adenocarcinomas. Secondary aim was to identify new prognostic histological features.
Methods:
All consecutive patients undergoing radical resection with a pathological diagnosis of primary lung adenocarcinoma were considered. All histological slides were reviewed for the study. Tumor-specific survival was considered as primary outcome. Statistical analysis included Kaplan-Meyer analysis and Cox regression to identify variables with significant Hazard Ratios (HR).
Results:
492 patients were considered between January 2002 and December 2013. 67.7% were male, mean age was 67.4 years, mean follow-up was 55 months. In a first multivariate Cox Regression Model the WHO 2004 grading was considered; gender [males vs females HR=1.7 95% CI (1.2-2.3), p=0.002], stage (p-trend <0.001), lymphoplasmacellular infiltrate [yes vs no HR=0.5 95% CI (0.3-0.8), p=0.001], and WHO 2004 grade (p-trend = 0.002) were independent prognostic factors of survival. In a second model the IASLC grading was considered; gender [HR=1.7 95% CI (1.2-2.4), p=0.002], stage (p-trend<0.001), lymphoplasmacellular infiltrate [HR=0.5 95% CI (0.3-0.8), p=0.001], and combined grading score according to Sica (p-trend=0.011) were maintained as independent prognostic factors.
Conclusion:
Tumor grading was an independent prognostic factor of survival in patients with adenocarcinoma undergoing lung resection both considering IASLC and WHO 2004 classifications. Lymphoplasmacellular infiltrate was significantly and favorably related to survival.
