By Hannah Scheucher
Metastases are the main cause of cancer-related death, responsible for roughly 90% of fatalities (Seyfried and Huysentruyt, 2013). In a nutshell, they are formed by cells that detach from the primary tumour and intravasate into the blood or lymph vessels to travel around the body before undergoing extravasation back into distant organs and tissues (Hanahan and Weinberg, 2000; Weinberg, 2014).
During primary tumour development, the cells undergoing neoplastic transformation start producing factors that can alter surrounding cells’ behaviour. These cells can also induce extracellular matrix (ECM) modification and angiogenesis to promote tumour growth (Liotta and Kohn, 2001). Interestingly, before metastasis occurs, primary tumour cells produce similar changes in distant organs to prepare an optimal environment for metastasis growth; these modified microenvironments are termed pre-metastatic niches (Peinado et al., 2017).
But how are these changes made to distant regions of the body? Some cells detach from the tumour and spread through the body as circulating tumour cells (Weinberg, 2014; Peinado et al., 2017). These cells can secrete soluble factors that have roles in changing pre-metastatic niches. Furthermore, extracellular vesicles called exosomes, that are between 30 and 150 nm in diameter, have been strongly implicated in the formation of pre-metastatic niches (Guo et al., 2019). These exosomes can carry various tumour-derived products such as protein, DNA, and messenger RNA, that affect target cells to produce the pre-metastatic niches.
The precise way these niches are formed varies depending on the tumour model being studied. However, one of the first common underlying changes that occurs is an increase in vascular disruption (Peinado et al., 2017). For example, vascular endothelial growth factor A, secreted either by tumour cells or tumour-associated cells, can activate focal adhesion kinase (FAK) in the target tissue. FAK then in turn disrupts the intercellular junctions between endothelial cells, causing vascular leakiness (Chen et al., 2012). This disruption of the endothelial barrier in blood vessels can contribute to facilitated invasion of circulating tumour cells to form metastases.
Blood clots are commonly seen in cancer and their presence has shown to cause some of the morbidities related with the disease (Weinberg, 2014). It was found that these platelet-rich clots surround tumour cells. Their presence reduces shear stress and interstitial flow, protecting the cells from physical damage and disruption as they circulate the body (Boccaccio and Medico, 2006) and facilitating their docking to start metastases (Peinado et al., 2017).
Tumour-derived soluble factors and exosomes subsequently act on accessible supportive tissues to allow pre-metastatic niches to form (Peinado et al., 2017). As described earlier, critical changes in the ECM take place to create an optimal environment for secondary tumour growth (Liotta and Kohn, 2001). This involves altering ECM molecules, or inducing production of new ECM molecules. For example, a study investigating pre-metastatic niches in a pulmonary cancer model (Hoshino et al., 2015) found that fibroblasts within the supportive tissue are activated to produce S100 proteins. These are a group of calcium-binding proteins involved in a multitude of cellular responses (Xia et al., 2018). In fibroblasts, S100 expression induces fibronectin upregulation – which attracts and provides a good scaffold of bone-marrow derived cells (BMDCs) (Hiratsuka et al., 2008; Peinado et al., 2017). BMDCs play an essential role in the pre-metastatic niche. It has recently been seen that in the absence of BMDCs no metastases were formed, suggesting a role in attracting circulating tumour cells to the forming niche (Kaplan et al., 2005).
Another protein whose expression by stromal cells is increased in the formation of a pre-metastatic niche is periostin (González-González and Alonso, 2018). Periostin, among other things, cross-links ECM molecules such as collagens, to integrin receptors (Kudo, 2011). This allows facilitated attachment of circulating tumour cells as well as transducing pro-proliferative and pro-survival signalling. Recently it has been shown that periostin is also involved in recruiting myeloid-derived suppressor cells (MDSCs) to the forming pre-metastatic niche (Wang et al., 2016). MDSCs are part of the immune system, preventing an exaggerated immune response in healthy individuals that can damage the body. In cancer, these cells are overly activated and permit cancer cells to avoid immune surveillance (Peinado et al., 2017).
By studying and understanding the molecular changes within the pre-metastatic niche, it is possible to develop treatments that prevent or reverse pre-metastatic niche formation. One study found that the recruitment of MDSCs was reduced in a pre-clinical lung cancer model upon epigenetic therapy (Lu et al., 2020). MDSCs are a critical factor in the formation of pre-metastatic niches in pulmonary cancer models in cancer. By administering DNA methyltransferase and histone deacetylase inhibitors following the surgical removal of primary tumours, MDSCs recruitment could be selectively inhibited, therefore reducing metastasis. The administered inhibitors induce their effect by down-regulating CCR2 and CXCR2 expression, which is necessary for attracting MDSCs to the niche. This attenuation of MDSCs led to increased periods of time in which mice were disease free as well as increasing overall life-expectancy (Lu et al., 2020). Other studies have also been able to limit metastatic progression via inhibition of pre-metastatic factors (Cicatiello et al., 2015; Xu et al., 2015).
Currently, imaging techniques such as PET and CT scans are unable to detect tumours smaller than 1 centimetre in size, meaning that metastases can be detected only after considerable growth has occurred (Peinado et al., 2017). Efforts are being made to improve the resolution of such diagnostic tools as well as allowing the detection of structural changes, such as tissue density, indicating pre-metastatic niche formation (Cox et al., 2015). Moreover, soluble factors and exosomes, found in the blood, may be used in future as molecular markers of pre-metastatic niches (Kosaka et al., 2007).
Metastases cause roughly 90 % of cancer-related death (Seyfried and Huysentruyt, 2013) and are thus a key step in cancer progression that must be targeted by cancer therapies. Understanding underlying concepts and mechanisms of metastasis such as the development of pre-metastatic niches will allow the design of new treatments to help increase quality of life and life expectancy.
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