Molecular Genetics of Metastasis

Abstract

Representing the least understood aspect of carcinogenesis, metastasis – the spread of cancer cells throughout the body – is frequently the cause of death from malignant growths. The underlying process of cancer cell dissemination is controlled by gene regulation programs in the tumour cells and in the host. The tumour cell intrinsic genetic programs of metastasis confer invasiveness and anchorage independence. The responsible genes are typically deregulated by aberrant expression or splicing. Metastasis suppressor genes, when expressed, can negatively regulate dissemination, and their loss of function may support tumour spread. Organ preference of metastasis depends on more complex tumour–host interactions. It is mediated by site‐specific molecular signals and formation of a premetastatic niche. The molecular genetics of metastasis has led to the development of diagnostic tests, based on gene expression profiles that help predict metastatic potential. Further, it has opened prospects for the targeting of the main culprits in antimetastasis therapy.

Key Concepts

  • Similar to other functions within cancer cells, the ability to metastasise is under positive and negative genetic controls.
  • Cancer metastasis is guided by two intrinsic characteristics of cancer cells, invasiveness and anchorage‐independent survival.
  • Cancer cell invasiveness constitutes the breaking of tumour cells through tissue barriers and represents the earliest manifestation of metastasis.
  • Invasiveness is mediated by aberrant expression or splicing of stress response genes, comprising secreted proteases, homing receptors, cytokine ligands and associated signalling molecules.
  • The acquisition of invasiveness by tumour cells is accompanied by a characteristic and reversible remodelling, called the epithelial–mesenchymal transition.
  • Cancers shed their tumour cells into the blood or lymph stream from the earliest stages of growth on; most cells die in the circulation.
  • Fully transformed cells can survive without anchorage for extended periods of time. They escape anoikis due to an upregulation in their energy metabolism.
  • The biologic activity of metastasis‐mediating gene products is extensively regulated by posttranscriptional mechanisms.
  • Besides the positive regulators of dissemination, there are gene regulation programs that antagonise cancer spread. Metastasis suppressor genes can curb dissemination and need to be inactivated for cancers to spread.
  • Gene expression programs of metastasis and specific tumour–host interactions encode consistent patterns of organ preference by individual malignancies. Circulating cancer cells can recognise target organs through the use of tissue markers and through establishing a premetastatic niche.

Keywords: metastasis; invasion; anoikis; homing receptor; cytokine; protease

Figure 1. Systemic tumour metastasis. The tumour suppressor P53 is defective in about half of all human cancers. Osteosarcomas develop spontaneously in mice with loss‐of‐function mutations in the trp53 gene, which encodes P53. These tumours metastasise to the liver (a) and the lungs (b). Metastasis formation in this context depends on the gene for the homing receptor CD44. In the absence of the cd44 gene, osteosarcoma metastasis is almost completely suppressed. The figure shows hematoxylin‐/eosin‐stained tissue sections. Reproduced from Weber et al. 2002.
Figure 2. Components of cancer metastasis. (a) Anchorage independence is an intrinsic requirement; (b) invasiveness is a property of the tumour cells, which becomes active through interactions with the host tissue (illustrated as the interactions by the C‐terminal and N‐terminal domains of the metastasis inducer osteopontin, OPN, with its cognate receptors); (c) the premetastatic niche is a complex interaction between the tumour and the host (shown as the example of a pulmonary metastasis).
Figure 3. Organ preferences in metastasis. Tumours of a particular organ origin tend to display consistent organ preference for metastasis. The figure shows common target organs and examples of the most important tumours that metastasise to them. Reproduced with permission from Zygote Media Group.
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Weber, Georg F(Jul 2017) Molecular Genetics of Metastasis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022447.pub2]