Metastasis describes a stage of cancer during which the initial tumor divides and leaves the initial site in the body where it arose, allowing it to begin growing in other parts of the body thereby disrupting local organ functionality and leading to multiorgan failure and death.

Mechanisms of Metastasis

Tumor metastasis tends to result from the synergistic activity of a number of cellular processes which ultimately conspire to produce cells which are able to take advantage of normal physiological processes in order to survive and spread throughout the body. Alterations in gene regulation, biochemical signaling, mechanosignaling, and cytoskeletal arrangement all tend to underlie the metastatic phenotype of invasive tumors, resulting in a difficult-to-treat cancer which utilizes a number of normal related biological mechanisms in aberrant ways to promote its own survival and spread.

Typically, as tumor cells become increasingly metastatic, they accumulate a number of mutations in various oncogenes which promote aberrant growth, motility, and survival through changes in gene expression and protein activity. A particularly noteworthy example of gene regulation gone awry is the fact that approximately half of all cancers contain mutations in the tumor suppressor transcription factor p53. Proper p53 functioning is necessary for cells to arrest the cell cycle in order to repair DNA damage or undergo apoptosis. Consequently, tumor cells expressing mutated p53 will not undergo proper DNA repair, allowing for the accumulation of other oncogenic mutations and the promotion of tumor metastasis.

As mutations in p53 alone are insufficient to promote tumorigenesis, it is unsurprising that invasive tumors tend to additionally have misregulations in various biochemical signaling pathways. Growth of normal cells is dependent on signals from the surrounding serum (serum dependence), however as cells become increasingly transformed they may begin to become serum-independent which entails the upregulation of endogenous growth factor receptors. This upregulation allows tumors to grow without receiving the normal extracellular signals required for such growth. For example, tumor cells have been shown to express upregulated levels of various chemokines and chemokine receptors such as the chemokine CSF-1 (colony stimulating factor 1). CSF-1 chemotactically attracts macrophages to the tumor site and causes these tumor-associated macrophages (TAMs) to alter their gene expression, promoting the expression of chemokines such as VEGF and SDF1α, both of which synergistically promote tumor invasiveness. TAMs additionally promote angiogenesis which is instrumental for metastatic progression, and a paracrine signaling loop between TAMs and tumor cells arises wherein their expression of epidermal growth factor and CSF-1, respectively, results in their mutual recruitment. This further promotes tumor invasiveness via p53 repression, vasodilation, and related mechanisms. If EGF receptor activity is inhibited, TAM-driven invasiveness in significantly abrogated, clearly demonstrating one way in which alterations in biochemical signaling within tumor cells can take advantage of normal physiological processes in order to promote metastasis.

In addition to defects in biochemical signaling mechanisms, tumor cells tend to develop a number of defects in mechanosensing and related signaling mechanisms which serve to promote tumor survival and subsequent metastasis. Normal cells are anchorage dependent such that if these cells detach from the ECM then proper integrin signaling does not occur and cells become apoptotic. Metastatic tumor cells, however, tend to be anchorage independent, and are consequently able to grow in non-native tissues and to proliferate through the bloodstream. An important mutation which often underlies anchorage independence and aberrant mechanosensing in tumor cells is the constitutive activation of focal adhesion kinase (FAK). In normal cells, FAK is activated in response to integrin signaling and recruits other proteins to sites of focal adhesions, leading to strengthening of the integrin-cytoskeleton linkage at this adhesion. In metastatic cells, constitutively active FAK results in results in defects in transduction of mechanosignals which causes cells to spread poorly on stiff surfaces but which may improve their ability to spread on surfaces whereupon these cells do not normally grow, thereby promoting metastasis. When FAK activity was inhibited using various inhibitors or FAK mutants, cells reverted to a less metastatic phenotype, demonstrating the fact that alterations in mechanosignaling are directly related to tumor progression in vitro.

Certain invasive tumor cells have additionally been shown to express constitutively high levels of Rho GTPases and Rho-associated kinase (ROCK). In non-transformed cells, Rho activation promotes the formation of stress fibers and focal adhesions and leads to proper cell reorientation in response to certain stimuli. In tumor cells, however, elevated Rho and ROCK expression results in improper mechanosensing with the end result of abnormal angiogenesis and cell reiorientation in response to mechanical stimuli. Inhibition of ROCK was shown to restore a less invasive phenotype to these cells, demonstrating the importance of proper mechanosensing in the prevention of metastasis . While changes in FAK and Rho expression are only two examples of ways in which disrupted mechanosensing can promote tumor invasiveness, these results clearly demonstrate ways in which tumors alter normal cellular signaling processes in a way which promotes their survival and spread.

In addition to these signaling changes, invasive tumors often undergo changes in their cytoskeletal dynamics, allowing these cells to better grow and invade tissues in response to extracellular stimuli. For example, in mouse mammary tumors it was shown that invasive cells tended to have upregulated levels of Cdc42, Arp2/3 associated proteins, capping protein, and cofilin. All of these proteins are involved in the regulation of actin dynamics, and the ultimate result of this upregulation in signaling was shown to be an increase in EGF-mediated chemotaxis due to an increase in actin polymerization at the site of EGF binding. Localized cofilin upregulation in particular is critical to tumor invasiveness due to its ability to create numerous barbed ends allowing for further actin filament formation. Another actin binding protein (ABP) which is often upregulated in malignant tumors is cortcactin, a protein which recruits Arp2/3 and promotes actin nucleation. Inhibition of cofilin or cortactin by siRNA significantly reduces tumor invasiveness, confirming the significance of altered regulation of ABPs in tumor metastasis.

These alterations in ABP activity, coupled with altered intracellular signaling, often lead to a number of structural changes in the cytoskeleton of tumor cells which promote tumor invasiveness. For example, some tumor cells form structures known as invadopodia which mimic the natural structures known as podosomes formed by monocytic cells. Invadopodia are able to deform the ECM in vivo due to the activity of associated matrix metalloproteinasesm thereby allowing motile metastatic tumor cells to move through the ECM relatively freely. As tumors are able to migrate, they inevitably become increasingly metastatic, underscoring the fact that alterations in ABP activity and cytoskeletal arrangement can directly promote a metastatic phenotype using physiologically normal cellular structures.

Ultimately, changes in gene regulation, signaling, and cytoskeletal dynamics all synergistically promote tumor metastasis in a manner which is also dependent upon signals from the tumor microenvironment. For example, the presence of mesenchymal stem cells in close association with otherwise weakly metastatic breast cancer cells promotes a paracrine signaling loop which results in enhanced metastatic spread. Recent studies have also demonstrated that metastatic tumor cells transplanted into the embryonic microenvironment of a zebrafish embryo do not undergo normal tumorigenesis, emphasizing the role of signaling from this microenvironment in tumor progression and metastasis. These results, coupled with the previously discussed role of TAMs in tumorigenesis, clearly indicate that the internal environment of a tumor cell is not the only determinant in metastatic potential, and that signals from various cell types the tumor microenvironment are equally critical to disease progression.

While individual mutations in oncogenes or integrin signaling pathways may promote a disorganized tumor phenotype, previous studies have shown that cooperation between ECM remodeling, oncogenic signaling, and improperly regulated mechanosignaling is necessary for tumors to become invasive. Individual mutations may result in increased susceptibility to future mutagenesis, however alone these mutations are insufficient to promote a metastatic phenotype. This clearly demonstrates that tumor metastasis is a complex process stemming from multiple misappropriations of normal physiological processes, all of which serve to promote tumor survival and invasiveness. By studying the different ways in which tumors make use of normal biological mechanisms, insight can be gained with respect to both these mechanisms and tumorigenesis, opening up numerous potential avenues for treatment.


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