scholarly journals Lung Microbiome Differentially Impacts Survival of Patients with Non-Small Cell Lung Cancer Depending on Tumor Stroma Phenotype

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 349 ◽  
Author(s):  
Olga Kovaleva ◽  
Polina Podlesnaya ◽  
Madina Rashidova ◽  
Daria Samoilova ◽  
Anatoly Petrenko ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Normal Tissue ◽  
Bacterial Load ◽  
Alpha Diversity ◽  
Tumor Stroma ◽  
Small Cell ◽  
Adjacent Normal Tissue ◽  
Small Cell Lung ◽  
Lung Microbiome ◽  
High Bacterial Load

The link between a lung tumor and the lung microbiome is a largely unexplored issue. To investigate the relationship between a lung microbiome and the phenotype of an inflammatory stromal infiltrate, we studied a cohort of 89 patients with non-small cell lung cancer. The microbiome was analyzed in tumor and adjacent normal tissue by 16S rRNA amplicon sequencing. Characterization of the tumor stroma was done using immunohistochemistry. We demonstrated that the bacterial load was higher in adjacent normal tissue than in a tumor (p = 0.0325) with similar patterns of taxonomic structure and alpha diversity. Lung adenocarcinomas did not differ in their alpha diversity from squamous cell carcinomas, although the content of Gram-positive bacteria increased significantly in the adenocarcinoma group (p = 0.0419). An analysis of an inflammatory infiltrate of tumor stroma showed a correlation of CD68, iNOS and FOXP3 with a histological type of tumor. For the first time we showed that high bacterial load in the tumor combined with increased iNOS expression is a favorable prognostic factor (HR = 0.1824; p = 0.0123), while high bacterial load combined with the increased number of FOXP3+ cells is a marker of poor prognosis (HR = 4.651; p = 0.0116). Thus, we established that bacterial load of the tumor has an opposite prognostic value depending on the status of local antitumor immunity.

scholarly journals LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 705 ◽  
Author(s):  
Cédric Zeltz ◽  
Elena Pasko ◽  
Thomas R. Cox ◽  
Roya Navab ◽  
Ming-Sound Tsao
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Xenograft Model ◽  
Tumor Stroma ◽  
Small Cell ◽  
Matrix Remodeling ◽  
Small Cell Lung

Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells. Using cancer-associated fibroblast (CAF) with either a knockdown or overexpression of LOXL1, we demonstrated a role for LOXL1 in collagen matrix remodeling and collagen fiber alignment in vitro and in vivo in a NSCLC xenograft model. As a consequence of collagen reorganization in NSCLC tumor stroma, we showed that LOXL1 supported tumor growth and progression. Our findings demonstrate that stromal LOXL1, under regulation of integrin α11, is a determinant factor of NSCLC tumorigenesis and may be an interesting target in this disease.

scholarly journals Mature Results of an Individualized Radiation Dose Prescription Study Based on Normal Tissue Constraints in Stages I to III Non–Small-Cell Lung Cancer

2010 ◽  
Vol 28 (8) ◽  
pp. 1380-1386 ◽  
Author(s):  
Angela van Baardwijk ◽  
Stofferinus Wanders ◽  
Liesbeth Boersma ◽  
Jacques Borger ◽  
Michel Öllers ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Dose ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Normal Tissue ◽  
Late Toxicity ◽  
Small Cell ◽  
Small Cell Lung ◽  
End Point ◽  
Grade 3

Purpose We previously showed that individualized radiation dose escalation based on normal tissue constraints would allow safe administration of high radiation doses with low complication rate. Here, we report the mature results of a prospective, single-arm study that used this individualized tolerable dose approach. Patients and Methods In total, 166 patients with stage III or medically inoperable stage I to II non–small-cell lung cancer, WHO performance status 0 to 2, a forced expiratory volume at 1 second and diffusing capacity of lungs for carbon monoxide ≥ 30% were included. Patients were irradiated using an individualized prescribed total tumor dose (TTD) based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8 Gy fractions twice daily. Only sequential chemoradiation was administered. The primary end point was overall survival (OS), and the secondary end point was toxicity according to Common Terminology Criteria of Adverse Events (CTCAE) v3.0. Results The median prescribed TTD was 64.8 Gy (standard deviation, ± 11.4 Gy) delivered in 25 ± 5.8 days. With a median follow-up of 31.6 months, the median OS was 21.0 months with a 1-year OS of 68.7% and a 2-year OS of 45.0%. Multivariable analysis showed that only a large gross tumor volume significantly decreased OS (P < .001). Both acute (grade 3, 21.1%; grade 4, 2.4%) and late toxicity (grade 3, 4.2%; grade 4, 1.8%) were acceptable. Conclusion Individualized prescribed radical radiotherapy based on normal tissue constraints with sequential chemoradiation shows survival rates that come close to results of concurrent chemoradiation schedules, with acceptable acute and late toxicity. A prospective randomized study is warranted to further investigate its efficacy.

scholarly journals Infiltration of immune competent cells into primary tumors and their surrounding connective tissues in mice

2020 ◽  
Author(s):  
Marlon Metzen ◽  
Michael Bruns ◽  
Wolfgang Deppert ◽  
Udo Schumacher
Keyword(s):  
Lung Cancer ◽  
Dendritic Cells ◽  
Adipose Tissue ◽  
Immune System ◽  
Cancer Cells ◽  
Tumor Stroma ◽  
Small Cell ◽  
Malignant Cells ◽  
Small Cell Lung ◽  
Tumor Capsule

Abstract Background: Due to the fact that a close physical contact between NK- and T-cells and cancer cells themselves is necessary to kill cancer cells, we wanted to study the distribution of immunocompetent cells in syngeneic and xenograft tumor models with immunodeficiency of the specific (T- and B-cells) immune system. Because of this approach we focused on the cells of the innate immune system. Methods: Paraffin wax embedded primary breast cancers from the syngeneic mouse WAP-T model and from xenografted tumors of breast, colon, melanoma, ovarian, neuroblastoma, pancreatic, prostate and small cell lung cancer were investigated for the infiltration of immunocompetent cells. The percentage of the labelled cells was semiquantitatively recorded and attributed to the following locations: adjacent adipose tissue, the tumor capsule, the intra-tumoral septae and the malignant cells themselves. The following markers were used: CD45 as a pan-leukocyte marker, BSA-I as a marker for dendritic cells, CD11b as a marker for NK cells and CD68 for macrophages. Results: Xenograft tumors: in relation to the localisation of CD45, CD11b positive, NK and dendritic cells, the highest score was found in the adjacent adipose tissue, followed by lesser infiltration in the malignant tissue. The detected numbers of CD45 positive cells differed between the tumor entities: few infiltrating cells in breast, small cell lung cancer and in neuroblastoma, a moderate infiltration in colon cancer, melanoma and ovarian cancer and strongest in prostate and pancreatic cancer.Syngeneic tumors: the highest score of CD45, CD11b positive, NK and dendritic cells were observed in the tumor capsule, followed by a lesser degree of infiltration of the cancer tissue itself.Conclusions: Our findings show in several neoplastic entities that the majority of immune competent cells are not directly located at the malignant cells but are present in the surrounding tumor stroma and connective tissue capsule. Hence the tumor stroma represents a considerable barrier for lymphocytes to come in direct contact with the malignant cells. Therefore strategies should be employed to make the tumor stroma more penetrable for immune cells in order to increase their efficacy.

The individuality of tumor-stroma interaction in non-small cell lung cancer: Insights from functional and molecular analyses

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11115-11115
Author(s):  
S. Gottschling ◽  
R. Kuner ◽  
M. Granzow ◽  
E. Chang Xu ◽  
T. Muley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Tumor Cells ◽  
Cell Lung Cancer ◽  
Stromal Cells ◽  
Tumor Stroma ◽  
Small Cell ◽  
Normal Lung ◽  
Small Cell Lung

11115 Background: Tumor-stroma interaction plays a significant role for malignant growth. Results from prostate and breast cancer rodent models show cancerogenic properties of tumor-associated and genetically altered stromal cells (SC) when combined with initiated or normal epithelium (Olumi et al., Cancer Res 1999, Kuperwasser et al., PNAS 2004). However, data on the mechanisms and sequels of tumor-stroma interaction in lung cancer are scanty. Methods: Here, we analyzed the functional and molecular sequels of cross-talk between the non-small cell lung cancer (NSCLC) cell lines A549, H23, and H1703 and primary stromal cells (SC) derived from matched normal lung tissue and tumors of newly diagnosed NSCLC patients. Tumor cells were kept in a non-contact co-culture system with SC and analyzed for alterations in proliferation, colony formation, migration, adhesion, invasion, chemosensitivity and gene expression by Affymetrix HG U133 Plus 2.0 arrays. Results: Exposure to SC altered cellular functions and gene expression profiles related to tumor growth, metastasis and response to therapy. Each cell line showed individual alterations that were hierarchically governed by the (1) type of tumor cell, (2) the SC donor and his histology (3) and the local origin of the SC (normal lung tissue vs. tumor-associated). Conclusions: This in vitro model demonstrates an individual pattern of tumor-stroma interaction in NSCLC that is determined by both, the properties of the tumor cells and those of the stromal environment. Thus, biomarker programs in NSCLC should also consider the stromal compartment. No significant financial relationships to disclose.

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