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.
Key Indexing Terms
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References
- Cancer statistics, 2015.CA Cancer J Clin. 2015; 65: 5-29
- Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective.AICR, Washington DC2007
- Tobacco smoke carcinogen and lung cancer.J Natl Cancer Inst. 1999; 91: 1194-1210
- The multistep nature of cancer development.Cancer Res. 1984; 44: 4217-4223
- 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
- Chemoprevention of cancer.A Cancer J Clin. 2004; 54: 150-180
- Molecular targets for breast cancer therapy and prevention.Nat Med. 2001; 7: 548-552
- The implications of angiogenesis for the biology and therapy of cancer metastasis.Cell. 1994; 79: 185-188
- Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction.Physiol Rev. 1996; 76: 69-125
- Lewis lung carcinoma progression is facilitated by TIG-3 fibroblast cells.Anticancer Res. 2013; 33: 3791-3798
- Human lung fibroblasts inhibit non-small cell lung cancer metastasis in ex vivo 4D model.Ann Thorac Surg. 2015; 100: 1167-1174
- Hepatocyte growth factor produced in lung fibroblasts enhances non-small cell lung cancer cell survival and tumor progression.Respir Res. 2017; 18: 1-10
- Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer.Carcinogenesis. 2006; 27: 1547-1555
- 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
- Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations.Cancer Res. 2008; 68: 9479-9487
- MRC-5 fibroblast-conditioned medium influences multiple pathways regulating invasion, migration, proliferation, and apoptosis in hepatocellular carcinoma.J Transl Med. 2015; 13: 1-13
- 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
- Cancer-associated fibroblasts: their characteristics and their roles in tumor growth.Cancers. 2015; 7: 2443-2458
- Cadherin switching: essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition.J Cell Sci. 2005; 118: 873-887
- Differential effects on lung cancer cell proliferation by agonists of glucocorticoid and PPARa receptors.Mol Carcinog. 2014; 53: 753-763
- Differential effects of MTSS1 on invasion and proliferation in subtypes of non-small cell lung cancer cells.Exp Ther Med. 2016; 12: 1225-1231
- Structure, recognition, and processing of cisplatin − DNA adducts.Chem Rev. 1999; 99: 2467-2498
- 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
- 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
- Confluence-depenent resistance to cisplatin in lung cancer cells is regulated by transforming growth factor-beta.Exp Lung Res. 2016; 42: 175-181
- Overcoming cisplatin resistance by mTOR inhibitor in lung cancer.Mol Cancer. 2005; 4: 1-10
- MET signalling: principles and functions in development, organ regeneration and cancer.Nat Rev Mol cell Biol. 2010; 11: 834-848
- 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
- Molecular predictors of sensitivity to the MET inhibitor PHA665752 in lung carcinoma cells.J Thorac Oncol. 2010; 5: 1317-1324
Article info
Publication history
Published online: September 06, 2022
Accepted:
August 31,
2022
Received:
March 5,
2022
Identification
Copyright
© 2022 Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation.
