We tried to identify all relevant studies irrespective of language. We searched PubMed, Medline, and Current Contents with a combination of the following terms: “metastasis”, “invasion”, “dissemination”, “chemokine”, “gene”, “protease”, “angiogenesis”, “lymphangiogenesis”, “signalling pathways”, “stroma”, “hypoxia”, “stem cell”, “host”, “gene signature”, “cell adhesion”, “extracellular matrix”, “microenvironment”, and “cancer therapy”. Studies were selected on the basis of recent
ReviewMetastasis: recent discoveries and novel treatment strategies
Introduction
Metastasis is the culmination of neoplastic progression. In their classic review, Hanahan and Weinberg describe six hallmarks of cancer.1 Besides immortality, abnormal growth regulation, self-sufficient growth, evasion of apoptosis, and sustained angiogenesis, invasion and metastasis are identified as distinguishing characteristics. However, although invasion through the basement membrane is the hallmark that objectively defines malignancy, not all neoplasms are invasive (eg, ductal carcinoma in situ of the breast and prostatic intraepithelial neoplasia), although they can progress towards malignancy. Similarly, the ability to metastasise is not an inherent property of all neoplastic cells. Some tumours are highly aggressive, forming secondary lesions with high frequency (eg, small cell carcinoma of the lung, melanoma, pancreatic carcinoma) whereas others rarely metastasise to distant sites despite being locally invasive (eg, basal cell carcinomas of the skin, glioblastoma multiforme).
Metastasis is generally described in terms of haematogenous (bloodborne) dissemination. However, secondary tumours can arise via spread through lymphatics (lymph node metastasis is a common feature of many carcinomas) or across body cavities (eg, ovarian carcinomas mainly establish secondary tumours by dissemination within the abdomen, rarely forming metastases via haematogenous spread). Cells can even migrate along the spaces between the endothelium and basement membrane or along neurons, as is the case in pancreatic carcinomas. The molecular and cellular mechanisms underlying these different proclivities are the topic of constant debate2 and intense research efforts because they have important implications for our ability to predict, identify, and eradicate life-threatening metastatic disease.
Section snippets
Progression towards an invasive phenotype
The process of metastasis begins before cells migrate from a primary tumour mass. Among the earliest characteristics of transformed cells are genetic and phenotypic instability. Cancer cells are more prone to mutation and phenotypic drift than their normal counterparts.3, 4, 5 Genetic instability, coupled with a Darwinian type of selection—survival of the fittest—results in populations resistant to normal homoeostatic growth controls, immune attack, and environmental restraints.6 The rate of
Angiogenesis and lymphangiogenesis
That tumour growth and progression is limited before vascularisation of the neoplastic mass is generally accepted.33 Vascularisation is achieved via neoangiogenesis,34 co-option of existing blood vessels,35 vasculogenic mimicry (in which poorly differentiated, highly malignant tumour cells can form a primitive vascular system),36 or a combination of these processes. Newly formed leaky capillaries can also serve as conduits for disseminating cells.
Hypoxia and activated oncogenes, including RAS,
When and how is metastatic potential determined?
Gene expression microarrays have provided hope for the vexing issue of identifying which tumours will or will not metastasise. Chemotherapy or hormonal therapy reduces the risk of distant metastases by about a third; however, 70–80% of breast cancer patients receiving adjuvant treatment would have survived without it. Because these patient populations cannot be accurately identified, they are treated unnecessarily.87 Several research groups have used microarrays to identify so-called poor
Conclusions and future prospects
Recent years have revealed exciting new insights into the molecular mechanisms of metastasis, although many questions remain (panel 2). We need to resolve the relative contributions of mutations in the seed cells (whether stem cells, their progeny, or both), epigenetic changes and microenvironmental influences, and not least inherited predisposition to cancer susceptibility and spread. Animal models have yielded important insights into the mechanisms of metastasis, but these must be measured
Search strategy and selection criteria
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