Abstract
Lung cancer is the leading cause of cancer related mortality worldwide, with non-small cell lung cancer (NSCLC) as the most prevalent form. Despite advances in treatment options including minimally invasive surgery, CT-guided radiation, novel chemotherapeutic regimens, and targeted therapeutics, prognosis remains dismal. Therefore, further molecular analysis of NSCLC is necessary to identify novel molecular targets that impact prognosis and the design of new-targeted therapies. In recent years, tumor “activated/reprogrammed” stromal cells that promote carcinogenesis have emerged as potential therapeutic targets. However, the contribution of stromal cells to NSCLC is poorly understood. Here, we show increased numbers of bone marrow (BM)-derived hematopoietic cells in the tumor parenchyma of NSCLC patients compared with matched adjacent non-neoplastic lung tissue. By sorting specific cellular fractions from lung cancer patients, we compared the transcriptomes of intratumoral myeloid compartments within the tumor bed with their counterparts within adjacent non-neoplastic tissue from NSCLC patients. The RNA sequencing of specific myeloid compartments (immature monocytic myeloid cells and polymorphonuclear neutrophils) identified differentially regulated genes and mRNA isoforms, which were inconspicuous in whole tumor analysis. Genes encoding secreted factors, including osteopontin (OPN), chemokine (C-C motif) ligand 7 (CCL7) and thrombospondin 1 (TSP1) were identified, which enhanced tumorigenic properties of lung cancer cells indicative of their potential as targets for therapy. This study demonstrates that analysis of homogeneous stromal populations isolated directly from fresh clinical specimens can detect important stromal genes of therapeutic value.
Highlights
Lung cancer is the leading cause of cancer related mortality worldwide, with an estimated 1.3 million new cases each year [1, 2]
Increased numbers of bone marrow hematopoietic cells infiltrate lung adenocarcinoma To evaluate the cellular landscape of tumor-activated BM stromal cells in human non-small cell lung cancer (NSCLC) we used stringent criteria for sample selection, preparation, and analysis
Using immunostaining and flow cytometry analysis we have shown increased recruitment of BM-derived stromal cells in tumor tissue compared with adjacent non-neoplastic lung tissue in NSCLC patients
Summary
Lung cancer is the leading cause of cancer related mortality worldwide, with an estimated 1.3 million new cases each year [1, 2]. Emerging studies from solid tumors including breast and prostate are beginning to recognize that carcinogenesis results from concerted interactions between genetically altered tumor epithelial cells and intratumoral stromal cells, resulting in an “activated/reprogrammed” stroma [9]. Consistent with this notion, analysis of enriched stromal compartments derived from human breast cancer revealed gene expression changes associated with cancer progression [10]. Administration of chemotherapy in combination with a macrophage antagonist (CSFR1 blockade) conferred synergy in breast cancer treatment [23] These studies, together with the clinical success of the antiangiogenic agent bevacizumab, a humanized monoclonal anti-VEGF antibody, provide compelling rationale for targeting the tumor microenvironment. Intratumoral stromal cells have emerged as attractive targets for anti-cancer therapy [11, 24]
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