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Fibroblast-derived conditioned media promotes lung cancer progression

  • John C. Greenwell
    Affiliations
    Department of Pharmacology & Toxicology, University of Louisville Health Sciences Center, Louisville, KY, United States
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  • Edilson Torres-Gonzalez
    Affiliations
    Department of Medicine, Division of Pulmonary, Allergy, and Critical Care and The Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA, United States
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  • Jeffrey D. Ritzenthaler
    Affiliations
    Department of Medicine, Division of Pulmonary, Allergy, and Critical Care and The Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA, United States
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  • Jesse Roman
    Correspondence
    Corresponding author at: Jesse, Roman, MD, Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, 834 Walnut Street, Suite 650, Philadelphia, PA 19107, United States.
    Affiliations
    Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY, United States

    Department of Medicine, Division of Pulmonary, Allergy, and Critical Care and The Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA, United States
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Published:September 06, 2022DOI:https://doi.org/10.1016/j.amjms.2022.08.019

      Abstract

      Lung cancer is the leading cause of cancer death in men and women in the United States. Recent studies have implicated the tumor microenvironment as a new chemotherapeutic target by demonstrating the importance of tumor cell-stromal interactions in cancer progression. However, the exact mechanisms by which tumor cell-stromal interactions drive lung cancer progression remain undefined, particularly in the lung. We suspect host fibroblasts represent an important component of the tumor microenvironment that drives tumor progression. We found that human non-small cell lung carcinoma cell lines show alterations in cell morphology, proliferation, migration, and colony formation on soft agar when exposed to fibroblast-conditioned media (FCM). Interestingly, FCM also promoted tumor cell resistance to cisplatin-induced apoptosis. These effects varied depending on the cancer cell line used. Similar observations were made when exposing murine Lewis Lung Carcinoma cells to conditioned media harvested from primary murine lung fibroblasts. Certain effects of FCM, but not all, could be prevented by using a cMET inhibitor. In vivo, we observed enhanced growth of the primary tumors when treated with FCM, but no changes in metastatic behavior. Although the identity of the stimulating agent(s) in the fibroblast-conditioned media was not unveiled, further studies revealed that the activity is more than one factor with a high-molecular weight (over 100 kDa). These studies implicate lung fibroblast-derived factors in lung cancer progression. These data suggest that targeting the lung tumor stroma alone, or in combination with other interventions, is a promising concept that warrants further study in the setting of lung cancer.

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      References

        • Siegel RL
        • Miller KD
        • Jemal A.
        Cancer statistics, 2015.
        CA Cancer J Clin. 2015; 65: 5-29
        • World Cancer Research Fund /American Institute for Cancer Research
        Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective.
        AICR, Washington DC2007
        • Hecht SS.
        Tobacco smoke carcinogen and lung cancer.
        J Natl Cancer Inst. 1999; 91: 1194-1210
        • Farber E.
        The multistep nature of cancer development.
        Cancer Res. 1984; 44: 4217-4223
        • Sato M
        • Vaughan MB
        • Girard L
        • Peyton M
        • Lee W
        • Shames DS
        • Ramirez RD
        • Sunaga N
        • Gazdar AF
        • Shay JW
        • Minna JD.
        Multiple oncogenic changes (K-RAS(V12), p53 knockdown, mutant EGFRs, p16 bypass, telomerase) are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells.
        Cancer Res. 2006; 66: 2116-2128
        • Tsao AS
        • Kim ES
        • Hong WK.
        Chemoprevention of cancer.
        A Cancer J Clin. 2004; 54: 150-180
        • Bange J
        • Zwick E
        • Ullrich A.
        Molecular targets for breast cancer therapy and prevention.
        Nat Med. 2001; 7: 548-552
        • Fidler I
        • Ellis L.
        The implications of angiogenesis for the biology and therapy of cancer metastasis.
        Cell. 1994; 79: 185-188
        • Rønnov-Jessen L
        • Petersen OW
        • Bissell MJ.
        Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction.
        Physiol Rev. 1996; 76: 69-125
        • Yamauchi Y
        • Izumi Y
        • Asakura K
        • Kawai K
        • Wakui M
        • Ohmura M
        • Suematsu M
        • Nomori H.
        Lewis lung carcinoma progression is facilitated by TIG-3 fibroblast cells.
        Anticancer Res. 2013; 33: 3791-3798
        • Mishra DK
        • Compean SD
        • Thrall MJ
        • Liu X
        • Massarelli E
        • Kurie JM
        • Kim MP.
        Human lung fibroblasts inhibit non-small cell lung cancer metastasis in ex vivo 4D model.
        Ann Thorac Surg. 2015; 100: 1167-1174
        • Kanaji N
        • Yokohira M
        • Nakano-Narusawa Y
        • Watanabe N
        • Imaida K
        • Kadowaki N
        • Bandoh S.
        Hepatocyte growth factor produced in lung fibroblasts enhances non-small cell lung cancer cell survival and tumor progression.
        Respir Res. 2017; 18: 1-10
        • Stabile LP
        • Lyker JS
        • Land SR
        • et al.
        Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer.
        Carcinogenesis. 2006; 27: 1547-1555
        • Takeuchi S
        • Wang W
        • Li Q
        • Yamada T
        • Kita K
        • Donev IS
        • Nakamura T
        • Matsumoto K
        • Shimizu E
        • Nishioka Y
        • Sone S
        • Nakagawa T
        • Uenaka T
        • Yano S.
        Dual inhibition of met kinase and angiogenesis to overcome HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer.
        Am J Pathol. 2012; 181: 1034-1043
        • Yano S
        • Wang W
        • Li Q
        • Matsumoto K
        • Sakurama H
        • Nakamura T
        • Ogino H
        • Kakiuchi S
        • Hanibuchi M
        • Nishioka Y
        • Uehara H
        • Mitsudomi T
        • Yatabe Y
        • Nakamura T
        • Sone S.
        Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations.
        Cancer Res. 2008; 68: 9479-9487
        • Ding S
        • Chen G
        • Zhang W
        • Xing C
        • Xu X
        • Xie H
        • Lu A
        • Chen K
        • Guo H
        • Ren Z
        • Zheng S
        • Zhou L.
        MRC-5 fibroblast-conditioned medium influences multiple pathways regulating invasion, migration, proliferation, and apoptosis in hepatocellular carcinoma.
        J Transl Med. 2015; 13: 1-13
        • Erez N
        • Truitt M
        • Olson P
        • et al.
        Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-??B-dependent manner.
        Cancer Cell. 2010; 17: 135-147
        • Shiga K
        • Hara M
        • Nagasaki T
        • et al.
        Cancer-associated fibroblasts: their characteristics and their roles in tumor growth.
        Cancers. 2015; 7: 2443-2458
        • Maeda M
        • Johnson KR
        • Wheelock MJ.
        Cadherin switching: essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition.
        J Cell Sci. 2005; 118: 873-887
        • Liang H
        • Kowalczyk P
        • Junco JJ
        • Klug-De Santiago HL
        • Malik G
        • Wei SJ
        • Slaga TJ
        Differential effects on lung cancer cell proliferation by agonists of glucocorticoid and PPARa receptors.
        Mol Carcinog. 2014; 53: 753-763
        • Ling DJ
        • Chen ZS
        • Liao Q De
        • et al.
        Differential effects of MTSS1 on invasion and proliferation in subtypes of non-small cell lung cancer cells.
        Exp Ther Med. 2016; 12: 1225-1231
        • Jamieson E
        • Lippard S.
        Structure, recognition, and processing of cisplatin − DNA adducts.
        Chem Rev. 1999; 99: 2467-2498
        • Santos NAG
        • Catão CS
        • Martins NM
        • et al.
        Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria.
        Arch Toxicol. 2007; 81: 495-504
        • Bartling B
        • Hofmann H-S
        • Silber R-E
        • et al.
        Differential impact of fibroblasts on the efficient cell death of lung cancer cells induced by paclitaxel and cisplatin.
        Cancer Biol Ther. 2008; 7: 1250-1261
        • Yokokura S
        • Kanaj N
        • Tadokoro A
        • et al.
        Confluence-depenent resistance to cisplatin in lung cancer cells is regulated by transforming growth factor-beta.
        Exp Lung Res. 2016; 42: 175-181
        • Wu C
        • Wangpaichitr M
        • Feun L
        • Kuo MT
        • Robles C
        • Lampidis T
        • Savaraj N.
        Overcoming cisplatin resistance by mTOR inhibitor in lung cancer.
        Mol Cancer. 2005; 4: 1-10
        • Trusolino L
        • Bertotti A
        • Comoglio PM.
        MET signalling: principles and functions in development, organ regeneration and cancer.
        Nat Rev Mol cell Biol. 2010; 11: 834-848
        • Ma PC
        • Jagadeeswaran R
        • Jagadeesh S
        • Tretiakova MS
        • Nallasura V
        • Fox EA
        • Hansen M
        • Schaefer E
        • Naoki K
        • Lader A
        • Richards W
        • Sugarbaker D
        • Husain AN
        • Christensen JG
        • Salgia R.
        Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer.
        Cancer Res. 2005; 65: 1479-1488
        • Matsubara D
        • Ishikawa S
        • Oguni S
        • et al.
        Molecular predictors of sensitivity to the MET inhibitor PHA665752 in lung carcinoma cells.
        J Thorac Oncol. 2010; 5: 1317-1324