As might be expected, large platelet count is associated with decreased survival in a wide range of cancers including breast, colorectal and lung cancer78
As might be expected, large platelet count is associated with decreased survival in a wide range of cancers including breast, colorectal and lung cancer78. order for any metastasis to occur, the intravasated malignancy cell must survive in the blood circulation, arrive at the prospective organ (seeding), extravasate into the parenchyma and display persistent growth1. Each of these phases is inefficient and some are rate limiting1,2. For example, senescence or apoptosis of malignancy cells in the stage of access into the metastatic site prevents the spread of the majority of circulating cells2C4. Seeding can occur to multiple organs, but metastatic tumours may grow in only one or a few5. There is also increasing evidence that in some cases malignancy cells can lay dormant for many years, and that seeding may occur several years before analysis of the primary tumour6C10. In another trend, termed angiogenic dormancy, there is a balance of proliferation and apoptosis that results in micrometastases that do not progress further11,12. The microenvironment BAY 61-3606 clearly suppresses the malignancy of these potentially metastatic cells10, and their re-activation to form a clinically relevant metastasis probably happens through perturbations in the microenvironment. Nevertheless, despite this evidence for early seeding and dormancy, tumour size and grade are the main predictors of metastasis, and this has been reinforced in recent studies in mouse models13 and by gene manifestation analysis that linked large tumour size with metastasis-enhancing gene signatures14. It has been hypothesized that this may be due to metastatic re- seeding to main tumours15. If this is the BAY 61-3606 case, nothing is currently known about the underlying mechanisms. Successful metastatic outgrowth therefore depends on the cumulative ability of malignancy cells to appropriate unique microenvironments at each step in the metastatic cascade: the primary tumour, systemic blood circulation and the final metastatic site. With this Review we discuss instructive, and in some cases dominating, functions for the microenvironment during the process of metastasis, with a particular focus on contributions from bone marrow-derived cells (BMDCs). TumourCstroma relationships at the primary site Tissues contain a plethora of cells that work in concert to effect normal physiology. These cells have positional identity so that their location is defined and their quantity constrained. Cancers possess lost these constraints through mutations in oncogenes and tumour suppressor genes. However, these tumour cells have not lost all their relationships with surrounding non-malignant cells or with the extracellular architecture. Indeed, these relationships are not static: they evolve along with the tumour, in particular through the recruitment of BMDCs. With this section we discuss evidence the microenvironment can exert inhibitory effects on even aggressive malignant cells. However, during their progression, tumours circumvent these inhibitory signals and instead exploit these surrounding cells to their own ends in processes that result in inappropriate growth, invasion and ultimately metastasis. Normal cells homeostasis Homeostasis in normal cells requires a tightly controlled balance of cell proliferation and death, which is definitely accomplished and managed through intercellular communication. An important regulator of normal cell behaviour and cells homeostasis is the surrounding extracellular matrix (ECM). The ECM offers many functions, including acting like a physical scaffold, facilitating relationships between different cell types, and providing survival and differentiation signals. BAY 61-3606 Maintaining organ homeostasis can prevent neoplastic transformation in normal cells by ensuring stable tissue structure, mediated by limited junction proteins and cell adhesion molecules such as 1 integrins and epithelial (E)-cadherin16,17. Insight into the dominance of the microenvironment over epithelial cell behaviour came from some of the earliest pioneering studies with this field. Mintz and colleagues showed the microenvironment of a mouse blastocyst not only suppressed the tumorigenicity of teratocarcinoma cells, but that those cells were stably reprogrammed, resulting in normal chimeric mice18. Subsequent studies indicated that this embryonic microenvironment is usually potent in its ability to reprogramme various malignancy cells, including metastatic cells, to a less aggressive phenotype19C23. Other groups have exhibited a particularly important role for stromal BAY 61-3606 fibroblasts in modulating the malignant progression of transformed epithelial cells. For example, BAY 61-3606 co-culture experiments showed that normal fibroblasts prevented the growth of initiated prostatic Rabbit Polyclonal to CDK7 epithelial cells24, and could even reverse the malignant phenotype.