Metastasis: recent discoveries and novel treatment strategies

doi:10.1016/S0140-6736(07)60781-8

The Lancet

Volume 369, Issue 9574, 19–25 May 2007, Pages 1742-1757

https://doi.org/10.1016/S0140-6736(07)60781-8 Get rights and content

Summary

Most cancer deaths are due to the development of metastases, hence the most important improvements in morbidity and mortality will result from prevention (or elimination) of such disseminated disease. Some would argue that treatments directed against metastasis are too late because cells have already escaped from the primary tumour. Such an assertion runs contrary to the significant but (for many common adult cancers) fairly modest improvements in survival following the use of adjuvant radiation and chemotherapy designed to eliminate disseminated cells after surgical removal of the primary tumour. Nonetheless, the debate raises important issues concerning the accurate early identification of clonogenic, metastatic cells, the discovery of novel, tractable targets for therapy, and the monitoring of minimal residual disease. We focus on recent findings regarding intrinsic and extrinsic molecular mechanisms controlling metastasis that determine how, when, and where cancers metastasise, and their implications for patient management in the 21st century.

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

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

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ReviewMetastasis: recent discoveries and novel treatment strategies

Summary

Introduction

Section snippets

Progression towards an invasive phenotype

Angiogenesis and lymphangiogenesis

When and how is metastatic potential determined?

Conclusions and future prospects

Search strategy and selection criteria

Cell

Lancet

Semin Cancer Biol

Biochim Biophys Acta

Biochim Biophys Acta

Curr Opin Cell Biol

Differentiation

Cancer Cell

Curr Opin Cell Biol

Curr Opin Cell Biol

J Biol Chem

J Biol Chem

Eur J Cancer

Blood

Mutat Res

J Biol Chem

Trends Immunol

Gynecol Oncol

Mod Pathol

Cancer Cell

Trends Cell Biol

Biochim Biophys Acta

Cancer Cell

Trends Cell Biol

Eur J Cancer

Eur J Cancer

Lancet

Cancer Detect Prev

Increasing metastatic potential is associated with increasing genetic instability of clones isolated from murine neoplasms

Proc Natl Acad Sci USA

The cellular basis of tumor progression

Int Rev Cytol

Implications of tumor progression on clinical oncology

Clin Exp Metastasis

Experimental systems for analysis of the malignant phenotype

Cancer Metastasis Rev

Development and biologic properties of malignant cell sublines and clones of a spontaneously metastasizing rat mammary adenocarcinoma

J Natl Cancer Inst

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Nature

Bone marrow cells in the ‘pre-metastatic niche’: within bone and beyond

Cancer Metastasis Rev

SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion

Nat Genet

Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition?

Cancer Res

Prostate cancer metastasis: role of the host microenvironment in promoting epithelial to mesenchymal transition and increased bone and adrenal gland metastasis

Prostate

Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways

Oncogene

The epithelial-mesenchymal transition: new insights in signaling, development, and disease

J Cell Biol

Complex networks orchestrate epithelial-mesenchymal transitions

Nat Rev Mol Cell Biol

Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation

Nature

The fallacy of epithelial mesenchymal transition in neoplasia

Cancer Res

Anoikis: cancer and the homeless cell

Nature

Metastasis: a question of life or death

Nat Rev Cancer

The role of apoptosis in tumor progression and metastasis

Curr Mol Med

Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB

Nature

The neurotrophic receptor TrkB in anoikis resistance and metastasis: a perspective

Cancer Res

Mutational analysis of the tyrosine kinome in colorectal cancers

Science

Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells

Review
Metastasis: recent discoveries and novel treatment strategies