Current and emerging concepts in tumour metastasis

Abstract

Disseminated cancer accounts for most deaths due to malignancy. Despite this, research has focused predominantly on tumour development and progression at the primary site. Recently, attention has shifted towards the field of tumour metastasis. Several new and exciting concepts that have emerged in the past few years may shed light on this complex area. The established canonical theory of tumour metastasis, as a process emerging from a stepwise accumulation of genetic events fuelled by clonal evolution, has been challenged. New evidence suggests that malignant cells can disseminate at a much earlier stage than previously recognized in tumourigenesis. These findings have direct relevance to clinical practice and shed new light on tumour biology. Gene-profiling studies support this theory, suggesting that metastatic ability may be an innate property shared by the bulk of cells present early in a developing tumour mass. There is a growing recognition of the importance of host factors outside the primary site in the development of metastatic disease. The role of the 'pre-metastatic niche' is being defined and with this comes a new understanding of the function of bone marrow-derived progenitor cells in directing the dissemination of malignant cells to distant sites. Current research has highlighted the crucial roles played by non-neoplastic host cells within the tumour microenvironment in regulating metastasis. These new concepts have wide-ranging implications for our overall understanding of tumour metastasis and for the development of cancer therapeutics.

The Interrelating Dynamics of Hypoxic Tumor Microenvironments and Cancer Cell Phenotypes in Cancer Metastasis

“…Invasion of the local stroma by the tumor cells where nutrient limitation is less may lead to the escape from cell stress [16]. Alternatively, establishment of a local vasculature supports not only the supply with nutrients but also the dissemination from the primary tumor into the blood stream as one of the first steps for tumor cell dissemination [20].…”

“…Considering a tumor diameter of approximately 1 cm at the time of diagnosis, the primary tumor has existed for approximately 10-12 years [20,44]. Hence, in these models the tumor has already existed 6-9 years until the proposed "early" dissemination has been implicated as a potential mechanism for metastasis [20,44,50].…”

“…As an alternative, during tumor hypoxia migratory active cell phenotypes evolve which share some attributes of "migratory stem cells" or epithelial mesenchymal transition (EMT) passed cells that are able to escape from the primary tumor into the blood stream [20,75]. After their passage through the blood followed by settlement into the bone marrow, a subset of DTC are assumed to be able to survive in the hypoxic microenvironment of the bone marrow even for decades [76].…”

“…Considering a tumor diameter of approximately 1 cm at the time of diagnosis, the primary tumor has existed for approximately 10-12 years [20,44]. Hence, in these models the tumor has already existed 6-9 years until the proposed "early" dissemination has been implicated as a potential mechanism for metastasis [20,44,50]. Even though "early" dissemination reduces the time for malignant transformation of the cells, it is conceivable that within this time span the cancer cells are able to colonize secondary organs [2,44].…”

Twist1 and Slug mediate H2AX-regulated epithelial-mesenchymal transition in breast cells

“…1 How to treat cancers arising from the spread of cancer cells to distant organs is a longstanding clinical challenge. Cells from primary tumors gain an invasive phenotype through a process widely known as epithelial-mesenchymal transition (EMT).…”