Although the incidence of lung cancer has decreased over the past several decades, it still remains higher than that of breast cancer, prostate cancer, and colon cancer combined,
and remains a significant threat worldwide. Tobacco use remains the number one risk factor, exposing an individual to a myriad of carcinogens, among other harmful compounds. The prevailing paradigm for decades has been that cells exposed to these and other carcinogens, acquire mutations in vital genes that over time lead to the development of tumors. However, it is now well-documented that mutations alone are not sufficient to account for tumor development and progression. In fact, a decreased incidence of colon and breast cancer has been observed through the use of non-steroidal anti-inflammatory drugs, , which suggests that factors other than cellular transformation are needed to cause tumor growth. This concept was first proposed in 1889, when Stephen Paget revealed his seed and soil hypothesis, which described a non-random pattern of metastasis in which cancer cells (“seeds”) depend on crosstalk with the microenvironment (“soil”) for growth and progression. In other words, metastasis from a primary tumor to distant organs is site specific, where the soil produces molecular factors appropriate and necessary for the seed’s survival. Since then, it has been shown that processes such as inflammation, angiogenesis, and paracrine signaling from stromal cells in the tumor microenvironment are vitally important for tumors to survive and progress. Fibroblasts are the predominant cell type in the tissue microenvironment and are largely responsible for the production of the extracellular matrix, in which they are embedded. Much attention has been given to the role of cancer-associated fibroblasts, which have been termed activated fibroblasts, identified by their expression of alpha-smooth-muscle actin. It is well-known that these activated fibroblasts can promote tumor progression. However, the role that normal lung fibroblasts play in the progression of lung cancer has been difficult to ascertain, with conflicting reports in the literature. For example, Yamauchi et al., showed that TIG-3 fibroblasts, when co-implanted with lung cancer cells, increased tumor growth at the site of injection and metastases to the lung, and that this effect was due, at least partly, to TGFβ-mediated interactions. These experiments, however, were performed in NOG mice, which are highly immunodeficient and thus must be interpreted carefully. In contrast, others have shown that normal lung fibroblasts play a role in inhibiting lung cancer progression. For example, Mishra et al., showed significantly fewer metastatic lesions in an ex vivo 4D acellular lung model when H460 cells were seeded with normal lung fibroblasts compared to carcinoma-associated fibroblasts. Others have shown an important role of fibroblast-derived hepatocyte growth factor (HGF) in lung cancer progression. , This has largely been shown in the setting of resistance to epidermal growth factor receptor tyrosine kinase inhibitors. ,
These data, among others, point to the complicated nature of tumor-stromal cell interactions, and warrant further research in this area, particularly in the lung. With the emerging practice of personalized medicine based on a patient’s genetic profile, perhaps the conflicting reports in the literature could be explained, at least in part, to differences in the genetic profile of the host and/or the various lung cancer cell lines used.
Here, we attempt to assess the role that normal, untransformed fibroblasts of the lung play in lung cancer progression in vitro and in vivo in immunocompetent animals using human and murine lung fibroblast and lung cancer cell lines.