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ScienceWeek
CANCER BIOLOGY: ON MECHANISMS OF METASTASIS
The following points are made by Patricia S. Steeg (Nature 2005 438:750):
1) During the process of metastasis, tumour cells move from the primary tumour to colonize another organ. But why do these mobile cells put down roots only in particular organs, or only at specific sites within an organ? The lungs and liver, for example, seem particularly popular secondary targets for tumour cells. Some studies imply that this "preference" might occur because, as they branch out within those organs, the blood vessels become very narrow, and the blood-borne tumour cells are trapped when they enter the fine capillary beds[1]. Other work has identified proteins that are specific to the cells lining the capillaries of certain tissues as possibly promoting metastasis formation[2]. A new report[3] provides another explanation. The authors show that tumour cells can mobilize normal bone-marrow cells, causing them to migrate to particular regions and change the local environment so as to attract and support a developing metastasis.
2) Metastasis is a sequential process, contingent on tumour cells breaking off from the primary tumour, travelling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumour cell regulate this behavior[4,5], and interactions between the tumour cell and host cells in the distant site are also significant. One of the best examples is the vicious cycle in bone metastasis, where tumour cells secrete parathyroid-hormone-related protein (PTHrP), which in turn activates normal bone cells to break down the bone matrix. This degradation releases embedded factors, such as transforming growth factor-beta (TGF-beta), that stimulate the tumour cells to proliferate and secrete more PTHrP. But are other cells involved in the metastatic process? And what are the earliest events at the metastatic site?
3) Kaplan et al[3] set up an experiment to track the movements of various cell populations as tumour cells metastasized in the lungs of live mice. The mice were irradiated to kill off all their bone-marrow cells, which were then replaced by bone-marrow cells tagged with green fluorescent protein; this made the cells easy to find under a microscope. Once the new bone-marrow cells were established, the mice were injected in the skin with lung carcinoma or melanoma cells, each marked with red fluorescent protein. The tumour cells were expected to form a primary tumour in the skin, and then to metastasize to the lungs. But the green bone-marrow-derived cells appeared in the lungs on days 12 14 after injection of the red cells -- well before any of the tumour cells had arrived in the lung. The red tumour cells turned up only on day 18 post-injection, and by day 23 micrometastases had formed, with more than 95% of the tumour cells being found in exactly the same sites as the bone-marrow-derived cells.
4) In a variation on this experimental theme, the authors injected the mice with the medium in which the melanoma cells had been cultured, rather than with the cells themselves. This also caused the bone-marrow cells to move to the animals' lungs, implying that the melanoma cells had secreted some factor into the surrounding solution that mobilized the bone-marrow cells. The mice were subsequently given red-tagged melanoma cells intravenously, and four days later 93% of these cells were found together with the bone-marrow cells in the lungs.
5) In the jargon of cancer biologists, tumors exist in a "niche"; this is analogous to an organism living in an ecological niche, in that the cancer is adapted to -- and taking advantage of -- its local physiological environment. Kaplan et al[3] explain their results by proposing that the tumour cells act to set up a pre-metastatic niche ready for their arrival in the lungs, sending bone-marrow cells in first to create a suitable environment for the tumour cells to settle in.
References (abridged):
1. Weiss, L. et al. J. Pathol. 150, 195 203 (1986)
2. Pasqualini, R. & Ruoslahti, E. Nature 380, 364 366 (1996)
3. Kaplan, R. N. et al. Nature 438, 820 827 (2005)
4. Steeg, P. Nature Rev. Cancer 3, 55 63 (2003)
5. Sawyer, T. K. Expert Opin. Invest. Drugs 13, 1 19 (2004)
Nature http://www.nature.com/nature
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MEDICAL BIOLOGY: ON TUMOR METASTASIS
The following points are made by A.E. Vernon and C. LaBonne (Current Biology 2004 14:R719):
1) Growing evidence demonstrates that many genes and proteins known to play essential roles during embryonic development are mutated or aberrantly expressed in cancerous cells. Studies of the genetic regulatory programs that control normal developmental processes can therefore provide essential insights into how such programs are inappropriately reactivated during tumorigenesis.
2) One widely studied developmental event that is also central to tumor progression is the epithelial-mesenchymal transition or EMT [1,2]. Cells undergoing an EMT experience transient structural changes resulting in loss of polarity and contact with neighboring cells and the acquisition of motility [3]. During normal development, EMTs are vital to the gastrulation movements that reorganize embryonic germ layers, as well as to the development of other migratory cell types, such as the neural crest [4,5]. Many of the molecular and phenotypic changes associated with cells undergoing developmental EMTs are also characteristic of the most aggressive metastatic cancer cells [1].
3) Most cancer-related deaths are caused, not by the primary tumor itself, but by subsequent metastases. While metastasis has been the subject of intense research for over a century, the molecular mechanisms governing the progression from a primary tumor cell to an invasive, malignant cell remain ill-defined. What is clear is that metastasis proceeds via a series of interrelated steps, each of which can be rate-limiting. These steps include: invasion; entry into systemic circulation ("intravasation"); movement from the circulatory system into a new host tissue ("extravasation"); and proliferation and growth of the secondary tumor. EMTs are a key event in the invasion step.
4) Loss of E-cadherin expression is emerging as one of the most common indicators of EMT onset. E-cadherin is required for the formation of stable adherens junctions and thus the maintenance of an epithelial phenotype. Because disruption of E-cadherin-mediated cell adhesion appears to be a central event in the transition from non-invasive to invasive carcinomas, several studies have focused on identifying and characterizing transcriptional repressors of E-cadherin expression in epithelial tumor cells. The most prominent factors to arise from these studies, including the related factors Slug and Snail, and the dEF1 protein SIP1, are best known for their roles in early embryogenesis, particularly during gastrulation and neural crest development.
References (abridged):
1. Thiery, J.P. (2003). Epithelial-mesenchymal transitions in development and pathologies. Curr. Opin. Cell Biol. 15, 740-746
2. Vincent-Salomon, A. and Thiery, J.P. (2003). Host microenvironment in breast cancer development: epithelial-mesenchymal transition in breast cancer development. Breast Cancer Res. 5, 101-106
3. Savagner, P. (2001). Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays 23, 12-23
4. Shook, D. and Keller, R. (2003). Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech. Dev. 120, 1351-1383
5. Locascio, A. and Nieto, M.A. (2001). Cell movements during vertebrate development: integrated tissue behaviour versus individual cell migration. Curr. Opin. Genet. Dev. 11, 464-469
Current Biology http://www.current-biology.com
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ON METASTASIS IN CANCER
The following points are made by J.E. Gershenwald and I.J. Fidler (Science 2002 296:1811):
1) The major cause of death from cancer is dissemination of the primary tumor, leading to formation of metastases that are resistant to conventional chemotherapy. Several factors account for the failure to treat metastases. First, neoplasms are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. Second, the process of metastasis selects for a small subpopulation of cells that preexist within a parental neoplasm. Third, and perhaps the greatest obstacle for therapy, is that the outcome of metastasis depends on multiple interactions between metastatic cells and homeostatic mechanisms that the tumor cells usurp (1). A better understanding of the molecular events that lead to metastasis and of the complex interactions between metastatic cells and host factors is essential for the design of more effective cancer therapies.(2)
2) To produce a metastasis, tumor cells must complete a series of sequential, interrelated steps. These include growth; neovascularization and lymphangiogenesis (development of new lymphatic vessels); invasion of the host stroma, blood vessels, and lymphatic system; survival in the circulation; arrest in small blood vessels; extravasation (migration out of blood vessels) into the parenchyma of organs; and continuous proliferation, which depends on establishing an adequate blood supply (angiogenesis) (1). Early clinical observations suggested that solid tumors (carcinomas) spread primarily via the lymphatic vessels and that mesenchymal (connective tissue) tumors spread mainly through the bloodstream. In truth, the lymphatic and vascular systems have numerous connections that allow disseminating tumor cells to pass rapidly from one system to the other (3).
3) Although the importance of the lymphatic system has been recognized for centuries (4), its involvement in the metastatic cascade has taken a back seat to the recent explosive interest surrounding the formation of tumor-associated blood vessels. Fortunately, recent work is beginning to elucidate the molecular mechanisms of lymphangiogenesis and lymphatic metastases. Among the unresolved controversies is the question of whether cancer cells in a primary tumor are transported to regional lymph nodes through intratumor lymphatic vessels. New techniques, such as intradermal administration of vital blue dye and radiolabeled colloid at the periphery of primary tumors, can identify the specific lymph nodes that receive afferent lymphatic drainage from the primary tumor site. These sentinel lymph nodes are the most likely to contain tumor metastases, which are often harbingers of future tumor development at sites distant from the lymph node (5).
References (abridged):
1. J. Fidler, in Clinical Oncology, M. D. Abeloff, J. O. Armitage, A. S. Lichter, J. E. Niederhuber, Eds. (Churchill Livingstone, New York, ed 2, 2000), pp. 29-53
2. T. P. Padera et al., Science 296, 1883 (2002).
3. Carr, Cancer Metastasis Rev. 2, 307 (1983)
4. R. S. Foster Jr., Surg. Oncol. Clin. N. Am. 5, 1 (1996)
5. J. E. Gershenwald et al., J. Clin. Oncol. 17, 976 (1999)
Science http://www.sciencemag.org
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