br Acknowledgements br The work was supported by the Board
The work was supported by the Board of Research in Nuclear Sciences, Department of Atomic Energy, Government of India, (Grant No.2009/34/38/BRNS/3206). The author, P. Raja is thankful to Centre for Research, Anna University, Chennai-25 for offering Anna Centenary Fellowships (Lr. No. CRF/ACRF/ Jan 2013/40). I also thank the Staff and Research Scholar, Dept. of Medical Physics, Anna University, Chennai-25.
Nutrition at the 71st Annual Meeting of Federation of American Societies for
Characterization of Distinct Populations of Carcinoma-Associated Fibroblasts from Non–Small Cell Lung Carcinoma Reveals a Role for ST8SIA2 in Cancer Cell Invasion1,2
* Cancer Center, Qilu Hospital of Shandong University, Jinan, China; †Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; ‡Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, UK, S1O 2HQ; §Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada; ¶Departments of Medical Biophysics, Toronto, Ontario, Canada; #Ontario Institute of Cancer Research, Toronto, Ontario, Canada
Carcinoma-associated fibroblasts (CAFs) are abundant stromal 12-O-tetradecanoyl phorbol-13-acetate in tumor microenvironment that are critically involved in cancer progression. Contrasting reports have shown that CAFs can have either pro- or antitumorigenic roles, indicating that CAFs are functionally heterogeneous. Therefore, to precisely target the cancer-promoting CAF subsets, it is necessary to identify specific markers to define these subpopulations and understand their functions. We characterized two CAFs subsets from 28 non–small cell lung cancer (NSCLC) patient tumors that were scored and classified based on desmoplasia [mainly characterized by proliferating CAFs; high desmoplastic CAFs (HD-CAF; n = 15) and low desmoplastic CAFs (LD-CAF; n = 13)], which is an independent prognostic factor. Here, for the first time, we demonstrate that HD-CAFs and LD-CAFs show different tumor-promoting abilities. HD-CAFs showed higher rate of collagen matrix remodeling, invasion, and tumor growth compared to LD-CAFs. Transcriptomic analysis identified 13 genes that were differentially significant (fold ≥1.5; adjusted P value b .1) between HD-CAFs and LD-CAFs. The top upregulated differentially expressed gene, ST8SIA2 (11.3 fold; adjusted P value = .02), enhanced NSCLC tumor cell invasion in 3D culture compared to control when it was overexpressed in CAFs, suggesting an important role of ST8SIA2 in cancer cell invasion. We confirmed the protumorigenic role of ST8SIA2, showing that ST8SIA2 was significantly associated with the risk of relapse in three independent NSCLC clinical datasets. In summary, our studies show that functional heterogeneity in CAF plays key role in promoting cancer cell invasion in NSCLC. r> Address all correspondence to: Roya Navab, Princess Margaret Cancer Research Tower / University Health Network, 101 College St. 11th Floor / Rm 11-301AM, Toronto, ON, M5G 1L7. E-mail: [email protected] 1 Conflicts of interest: The authors declare no potential conflicts of interest.
wrote the paper. 3 J. H. and C. Z. contributed equally to this work.
© 2019 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1476-5586
Tumor stroma is no longer seen solely as physical support for mutated epithelial cells but as an important modulator and even a driver of tumorigenicity in non–small cell lung cancer (NSCLC) [1,2]. One of the most consistent histological features of cancer cell invasion is the changes in tumor stroma recognized as desmoplasia. Desmoplasia is characterized by the activation of stromal fibroblasts into carcinoma-associated fibroblasts (CAFs), increased matrix protein disposition, new blood vessel formation, and immune cell infiltration. Desmo-plasia is associated with tumor aggressiveness, which includes tumor cell growth, invasion, and metastases, suggesting that specific cellular or ECM components of desmoplasia promote tumor progression and metastasis [3–5]. Within the tumor stroma milieu, CAFs are the major stromal components in many types of malignancies that play a crucial role in tumor development [6–11] and are potential therapeutic targets for cancer . However, recent studies suggest that CAFs are heterogeneous and contain different subpopulations with distinct phenotypes and functions, which hinder their application in diagnosis and targeted therapy [12,13]. Although significant prognostic impacts of CAFs have been studied in various tumors, including breast and lung cancers, whether CAFs are associated with good or poor prognosis is contradictory in different studies . These studies present encouraging proof-of-concept findings that CAFs could be exploited for prognostication; however, they also highlight the difficulties to conclusively define an “activated stroma” and to identify the individual factors involved in clinically relevant tumor-stroma interactions. Basically, although it is generally thought that CAFs promote tumor progression, targeting alpha smooth muscle actin (α-SMA)–expressing CAFs leads to disease exacerbation in cohort of pancreatic cancer patients  and in a mouse model of pancreatic cancer [16,17], suggesting that different fibroblast subsets may exert opposite functions in cancer progression. For example, in oral squamous cell carcinoma, two CAF subtypes have been identified that have differential tumor-promoting capability . Therefore, to precisely target the cancer-promoting CAF subsets, it is necessary to identify specific markers to define these subpopulations and understand their functions.