Cancer develops when cells in the body acquire mutations that allow them to grow and divide quickly and uncontrollably. At some stage of the disease, these cancer cells develop the ability to spread throughout the body. This spreading process, called metastasis, is responsible for most cancer-related deaths in humans, yet there is no treatment targeting the metastasis process.
Numerous studies have examined human clinical samples and/or tumor-derived cell lines to discern the mechanisms of metastasis, and have identified specific genes as well as the role of the tumor micro-environment.
It should be noted that anecdotal reports suggest that metastases may occur under circumstances that would promote inflammation such as surgery (Tohme et al., 2017) or during an infection (Smith and Kang, 2013). The authors of the following study discovered that the proteins MYC and TWIST1 cause metastases by activating a transcription program in cancer cells which induces cytokines which in turn allow recruitment and polarization of macrophages.
Liver cancer cells with high levels of MYC (red) and TWIST1 spreading into an infiltrated lung of macrophages (green) that have been converted to a tumor-friendly state. Image credit: Nia Adeniji (CC BY 4.0)
Myc is a proto-oncogene that is over-expressed in certain human cancers. When subjected to mutations or overexpression, it stimulates cell proliferation and behaves like an oncogene.
TWIST1 is a transcription factor which in humans is encoded by the TWIST1 gene and is involved in the metastasis process. Inactivation of Twist by small interfering RNAs or a chemotherapeutic approach has been demonstrated in vitro. Thymoquinone, which is isolated from Nigella sativa (black cumin), downregulates the transcription factor TWIST1.
However, to date, there are very few in vivo models in which the progression from non-metastatic cancer to metastatic cancer can be studied. The researchers therefore generated a new model of conditional transgenic mouse metastasis that has characteristics that are complementary to existing model systems. This model animal systematically develops hepatocellular carcinoma, or hepatocarcinoma.
It is the most common type of primary liver cancer in adults and the most common cause of death in people with cirrhosis Their new model has allowed them to study tumor-host interactions during malignant progression in an immunocompetent host. In their model, more than 90% of the mice predictably develop extrahepatic metastases. They believed that their model has general relevance for all human cancers and that it will be useful in developing new therapies that block cancer metastases.
In this animal model of metastasis, the researchers demonstrated that the expression of MYC and Twist1 is necessary to trigger metastasis. They discovered that MYC and Twist1 bind to promoters of the human and mouse Ccl2 and Il13 genes. MYC and Twist1 coordinate to regulate a set of cytokines, including Ccl2 and Il13, which are both necessary and sufficient to cause metastasis.
Their results suggest that MYC and Twist1 may contribute to metastases by a transcriptional induction mechanism of a cytokinoma which activates macrophages. They note that their observations are consistent with a multitude of reports that innate immunity contributes to metastasis.
They propose as a possible general explanation of their results that the overexpression of MYC and TWIST1 in a tumor, activates an embryonic program of activation of innate immune cells and of cellular invasion. Indeed MYC and TWIST1 cooperate during embryogenesis. These two transcription factors have also been shown to modulate inflammation transcriptionally during embryogenesis. The microenvironmental changes induced by inflammation are necessary to allow mesodermal cells to migrate to their destination.
Researchers suggest that personalized therapy that combines inhibition of CCL2 and IL13 is likely to be effective, and that stratification of patients by cytokine expression may help guide treatment.