Lung Metastases

Pathogenesis of Lung Metastasis

The development of lung metastases may occur by a number of postulated mechanisms, involving interplay between both immunologic and hematologic processes. Although the precise mechanisms by which metastatic spread to the lung occurs has not been fully elucidated, the general processes that may underlie the development of lung metastasis include immune escape, invasion or intravasation into blood vessels, and movement through the circulatory system, culminating in extravasation of tumor cells into the lungs. Laboratory studies have indicated that a number of factors in the tumor microenvironment may contribute to the development of lung metastasis, including vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), platelet-derived endothelial cell growth factor (PD-ECGF), and/or basic fibroblast growth factor (bFGF), as seen in melanoma models. For example, the published results of studies have demonstrated that depletion of carcinoma-associated fibroblasts via changes in bFGF may significantly decrease the number of lung metastases.

In addition, tumor cells themselves may play a role in preparing a site for metastatic invasion, by manipulating normal cellular processes. For instance, hematopoietic progenitor cells expressing VEGFR1 form cellular clusters in premetastatic sites, where they have been found to produce very late antigen 4 (VLA-4), which is involved in preparing the site for potential metastatic spread. From here, tumor-specific growth factors may upregulate fibronectin in fibroblasts located at premetastatic sites, which are then primed to interact with VLA-4, thus supporting the process of tumor invasion. Moreover, tumor cells may activate chemokines that have the capability of attracting both immune cells and tumor cells to the lungs. VEGF-A, tumor necrosis factor–α (TNF-α), and transforming growth factor–β (TGF-β) induce expression of inflammatory chemokines S100A8 and S100A9, which in turn attract macrophage antigen 1 (MAC-1)–positive myeloid cells to the premetastatic lung and cause tumor cells to acquire migration activity along with pseudopodia, used for lung invasion. Other chemokine mechanisms implicated in lung metastatic spread involve travel of CCR4+ tumor cells along a chemokine gradient, and release of the chemokine CCL5 from mesenchymal cells to enhance motility and invasion, as seen in breast cancer metastatic models. Thus tumor cells may assist the process of metastatic spread by creating a chemokine gradient to attract both benign and malignant cells to the area. Another mechanism by which tumor cells may leverage the immune system to assist in both tumor survival and metastatic spread includes reduction in the number of cytotoxic T cells. Temporarily entrapped tumor cells can recruit immune cells such as neutrophils to remain in the lungs via IL-8, which increases B2 integrin on the surface of neutrophils, allowing intercellular adhesion molecule 1 (ICAM-1) on the surface of tumor cells to anchor invading cells within the lung. A decrease in IL-8 secretion is thus associated with a commensurate decrease in the incidence of lung metastasis.

Another group of mechanisms focuses on the ways in which lung metastasis develops, through promotion of angiogenesis and alteration of immune cell activity. Once tumor cells arrive in the lung with associated stromal components and myeloid cells, their ability to influence angiogenesis has been found to contribute significantly to their lethality. In this context, myeloid progenitor cells may act as critical regulators of tumor survival that support the development of both micrometastasis and macrometastasis. Tumor cells induce expression of transcription factor inhibitors of differentiation (Id) in myeloid progenitor cells, which in turn induces angiogenesis. This mechanism was seen most notably in breast cancer models, in which both Id1 and Id3 are required for sustained cell proliferation of lung metastasis. Myeloid-derived suppressor cells (MDSCs) have also been shown to be implicated in this process via the TGF-β pathway, and this population of cells has also been seen to travel alongside tumors cells, helping them evade the immune system and inducing angiogenesis. TNF and TNFR2 play a major role in metastasis via the recruitment of both tumor and T regulatory (Treg) cells to the lung, along with recently discovered regulatory B-cell populations, which convert CD4+ T cells to Tregs. Thus by both enhancing angiogenesis and altering the composition of immune cell populations, tumor cells may gain the ability to alter the tumor microenvironment at the metastatic site, thereby creating an environment that is more habitable to malignancy.

In addition to these processes, the presence of the primary tumor itself may also support the expression of appropriate genes, cell surface receptors, and cellular processes, in order to facilitate metastatic spread to the lungs. A dominant negative mutation of caveolin-1, a principal structural protein present in nonmuscle cells, is detected in up to 16% of breast cancer samples, and a complete loss of caveolin-1 is associated with increased tumorigenesis and lung metastasis, possibly via loss of negative regulation and transcriptional suppression of certain genes. Tumor cells that show increased affinity for lung endothelial cell adhesion molecule-1 (Lu-ECAM-1) on lung blood vessels have an increased propensity for lung metastasis, and use of antibodies to block this adhesion molecule was shown to reduce lung metastasis by up to 90% in a B16-F10 melanoma model. High expression of transferrin receptors on the surface of tumor cells has also been shown to increase the propensity for metastasis to the lung compared with poorly metastatic cells. TGF-β expression has been shown to confer the ability to prime tumors for lung invasion, via induction of angiopoietin-like 4 (Angptl4), a protein that disrupts vascular endothelial cell-cell junctions. Other pathways implicated in this process include expression of the epidermal growth factor receptor (EGFR) ligand epiregulin, cyclooxygenase 2 (COX-2), and matrix metalloproteinases 1 and 2 (MMP1, MMP2), which in concert have the ability to induce angiogenesis, along with tumor cell intravasation and extravasation, and knockdown of these pathways associated with a statistically significant decrease in lung metastasis. In colorectal cancer (CRC), the expression of KRAS , which alters cytoskeletal organization, proliferation, and vesicle trafficking, is associated with almost double the incidence of lung metastasis compared with liver metastasis. Thus by expressing the appropriate genes and altering their own cellular activity, tumor cells may be able to maximize their metastatic potential to the lungs.

Effect of Diet on Lung Metastasis

Recent studies have demonstrated that host diet in the setting of a cancer may play a role in tumor growth and metastasis. Diets high in omega-6 fatty acids, such as linoleic acid, have been linked to statistically higher rates of visible lung metastasis in mice injected with human breast cancer cells. The effect of a high–omega-6 diet can be negated in mice fed high-fat diets through administration of indomethacin, suggesting that arachidonic acid metabolites such as prostaglandin E (PGE) play a major role in enhancing the likelihood of metastatic spread. Interesting to note, conjugated linoleic acid has been shown to also negate this effect and may be almost as effective as indomethacin. Conversely, omega-3 fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, have been shown to reduce lung metastasis in CRC, breast carcinoma, and melanoma, possibly through suppression of tumor eicosanoid biosynthesis, influences on gene expression leading to changes in levels of various factors, alteration of estrogen metabolism, and alterations in production of free radicals. Further studies in this area are required to assess the clinical implications of these data, such as the potential role for omega-3 fatty acid supplementation to reduce risk of metastatic spread to the lungs.