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For the musical composition, see Metastaseis (Xenakis). For the 2009 film, see Metastases (film).
Metastasis
DiseasesDB
28954
MedlinePlus
002260
Metastasis, or metastatic disease, is the spread of a cancer from one organ or part to another non-adjacent organ or part. The new occurrences of disease thus generated are referred to as metastases (sometimes abbreviated mets)[1][2] It was previously thought that only malignant tumor cells andinfections have the capacity to metastasize; however, this is being reconsidered due to new research.[3] In origin metastasis is a Greek word meaning "displacement", from , meta, "next", and , stasis, "placement". The plural is metastases.
Cancer occurs after a single cell in a tissue is progressively genetically damaged to produce cells with uncontrolled proliferation. This uncontrolled proliferation, mitosis, produces a primary tumor. The cells which constitute the tumour eventually undergo metaplasia, followed by dysplasia thenanaplasia, resulting in a malignant phenotype. This malignant phenotype allows for intravasation into the circulation, followed by extravasation to a second site for tumorigenesis. Some cancer cells acquire the ability to penetrate the walls of lymphatic and/or blood vessels, after which they are able to circulate through thebloodstream (circulating tumor cells) to other sites and tissues in the body. This process is known (respectively) as lymphatic or hematogeneousspread. After the tumor cells come to rest at another site, they re-penetrate the vessel or walls and continue to multiply, eventually forming another clinically detectable tumor. This new tumor is known as a metastatic (or secondary) tumor. Metastasis is one of three hallmarks of malignancy (contrast benign tumors).[4] Most neoplasms can metastasize, although in varying degrees (e.g., basal cell carcinoma rarely metastasize).[4] When tumor cells metastasize, the new tumor is called a secondary or metastatic tumor, and its cells are similar to those in the original tumor. This means, for example, that, if breast cancer metastasizes to the lungs, the secondary tumor is made up of abnormal breast cells, not of abnormal lung cells. The tumor in the lung is then called metastatic breast cancer, not lung cancer.
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2.2.1 1. Transcoelomic 2.2.2 2. Lymphatic spread 2.2.3 3. Haematogenous spread 2.2.4 4. Transplantation or implantation
2.3 Organ-specific targets 2.4 Metastasis and primary cancer 2.5 Common sites of origin
Cut surface of a liver showing multiple paler metastatic nodules originating frompancreatic cancer
Initially, nearby lymph nodes are struck early.[5] The lungs, liver, brain, and bones are the most common metastasis locations from solid tumors.[5]
In lymph nodes, a common symptom is lymphadenopathy Lungs: cough, hemoptysis and dyspnea[5] (shortness of breath) Liver: hepatomegaly (enlarged liver), nausea[5] and jaundice[5] Bones: bone pain,[5] fracture of affected bones[5] Brain: neurological symptoms such as headaches,[5] seizures,[5] and vertigo.[5]
Although advanced cancer may cause pain, it is often not the first symptom. Some patients, however, don't show any symptoms.[5] When the organ gets a metastatic disease it begins to shrink until its lymph nodes burst, or undergo lysis.
random, with different types of cancer tending to spread to particular organs and tissues at a rate that is higher than expected by statistical chance alone.[7] Breast cancer, for example, tends to metastasize to the bones and lungs. This specificity seems to be mediated by soluble signal molecules such as chemokines[8] and transforming growth factor beta.[9] The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressors, of which about a dozen are known.[10] Human cells exhibit 3 kinds of motion: collective motility, mesenchymal-type movement, and amoeboid movement. Cancer cells often opportunistically switch between different kinds of motion. Some cancer researchers hope to find treatments that can stop or at least slow down the spread of cancer by somehow blocking some necessary step in one or the other or both kinds of motion.[11] Cancer researchers studying the conditions necessary for cancer metastasis have discovered that one of the critical events required is the growth of a new network of blood vessels, called tumorangiogenesis.[12] It has been found that angiogenesis inhibitors would therefore prevent the growth of metastases.[4] There are several different cell types critical to tumor growth. In particular endothelial progenitor cells are a very important cell population in tumor blood vessel growth. This finding was published in the journals Science (2008) and Genes and Development (2007) together with the fact that endothelial progenitor cells are critical for metastasis and angiogenesis.[13][14] The importance of endothelial progenitor cells in tumor growth, angiogenesis and metastasis has been confirmed by a recent publication in Cancer Research (August 2010). This seminal paper has demonstrated that endothelial progenitor cells can be marked using the Inhibitor of DNA Binding 1 (ID1). This novel finding meant that investigators were able to track endothelial progenitor cells from the bone marrow to the blood to the tumor-stroma and even incorporated in tumor vasculature. This finding of endothelial progenitor cells incorporated in tumor vasculature proves the importance of this cell type in blood vessel development in a tumor setting and metastasis. Furthermore, ablation of the endothelial progenitor cells in the bone marrow lead to a significant decrease in tumor growth and vasculature development. Therefore endothelial progenitor cells are very important in tumor biology and present novel therapeutic targets.[15] NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at the basis of metastasis formation. Indeed NFAT1 (NFATC2) and NFAT5 are pro-invasive and pro-migratory in breast carcinoma[16][17] and NFAT3 (NFATc4) is an inhibitor of cell motility.[18] NFAT1 regulates the expression of the TWEAKR and its ligand TWEAK with the Lipocalin 2 to increase breast cancer cell invasion NFAT3 inhibits Lipocalin 2 expression to blunt the cell invasion.
[18] [19]
and
Main sites of metastases for some common cancer types. Primary cancers are denoted by " ...cancer" and their main metastasis sites are denoted by "...metastases".[20]
Lymph node with almost complete replacement by metastatic melanoma. The brown pigment is focal deposition of melanin
from bone. Malignant melanoma spreads to the brain, presumably because neural tissue and melanocytes arise from the same cell line in the embryo.[23] In 1928, James Ewing challenged the "seed and soil" theory and proposed that metastasis occurs purely by anatomic and mechanical routes. This hypothesis has been recently utilized to suggest several hypotheses about the life cycle of circulating tumour cells (CTCs) and to postulate that the patterns of spread could be better understood through a 'filter and flow' perspective. [24]
Lung Breast Skin: melanoma (other skin tumors rarely metastasize) Colon Kidney Prostate Pancreas Cervix
The cells in a metastatic tumor resemble those in the primary tumor. Once the cancerous tissue is examined under a microscope to determine the cell type, a doctor can usually tell whether that type of cell is normally found in the part of the body from which the tissue sample was taken. For instance, breast cancer cells look the same whether they are found in the breast or have spread to another part of the body. So, if a tissue sample taken from a tumor in the lung contains cells that look like breast cells, the doctor determines that the lung tumor is a secondary tumor. Still, the determination of the primary tumor can often be very difficult, and the pathologist may have to use several adjuvant techniques, such as immunohistochemistry, FISH (fluorescent in situ hybridization), and others. Despite the use of techniques, in some cases the primary tumor remains unidentified. Metastatic cancers may be found at the same time as the primary tumor, or months or years later. When a second tumor is found in a patient that has been treated for cancer in the past, it is more often a metastasis than another primary tumor. It was previously thought that most cancer cells have a low metastatic potential and that there are rare cells that develop the ability to metastasize through the development of somatic mutations.[26] According to this theory, diagnosis of metastatic cancers is only possible after the event of metastasis. Traditional means of diagnosing cancer (e.g. a biopsy) would only investigate a subpopulation of the cancer cells and would very likely not sample from the subpopulation with metastatic potential.[27] The somatic mutation theory of metastasis development has not been substantiated in human cancers. Rather, it seems that the genetic state of the primary tumor reflects the ability of that cancer to metastasize.[27] Research comparing gene expression between primary and metastatic adenocarcinomas identified a subset of genes whose expression could distinguish primary tumors from metastatic tumors, dubbed a "metastatic signature."[27] Up-regulated genes in the signature include: SNRPF, HNRPAB, DHPS and securin. Actin, myosin and MHC class II down-regulation was also associated with the signature. Additionally, the metastatic-associated expression of these genes was also observed in some primary tumors, indicating that cells with the potential to metastasize could be identified concurrently with diagnosis of the primary tumor.[28] Expression of this metastatic signature has been correlated with a poor prognosis and has been shown to be consistent in several types of cancer. Prognosis was shown to be worse for individuals whose primary tumors expressed the metastatic signature.[27] Additionally, the expression of these metastatic-associated genes was shown to apply to other cancer types in addition to adenocarcinoma. Metastases of breast cancer, medulloblastoma and prostate cancer all had similar expression patterns of these metastasisassociated genes.[27] The identification of this metastasis-associated signature provides promise for identifying cells with metastatic potential within the primary tumor and hope for improving the prognosis of these metastatic-associated
cancers. Additionally, by identifying the genes whose expression is changed in metastasis offers potential targets to inhibit metastasis.[27]
Cut surface of a humerussawn lengthwise, showing a large cancerousmetastasis (the whitish tumor between the head and the shaft of the bone)
Micrograph of thyroid cancer (papillary thyroid carcinoma) in a lymph node of the neck. H&E stain
Metastasis proven by liverbiopsy (tumor (adenocarcinoma) - lower two-thirds of image). H&E stain.
2.
^ Chiang AC, Massagu J (December 2008). "Molecular basis of metastasis". The New England Journal of Medicine 359 (26): 281423. doi:10.1056/NEJMra0805239.PMID 19109576.
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^ Podsypanina K, Du YC, Jechlinger M, Beverly LJ, Hambardzumyan D, Varmus H (September 2008). "Seeding and Propagation of Untransformed Mouse Mammary Cells in the Lung".Science 321 (5897): 18414. doi:10.1126/science.1161621. PMC 2694414.PMID 18755941.
4.
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Kumar, Vinay; Abbas, Abul K; Fausto, Nelson; Robbins, Stanley L; Cotran, Ramzi S
(2005). Robbins and Cotran pathologic basis of disease (7th ed.). Philadelphia: Elsevier Saunders. ISBN 978-0-7216-0187-8. 5. ^
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National Cancer Institute: Metastatic Cancer: Questions and Answers. Retrieved on 2008-
11-01 6. 7. ^ "Metastatic Cancer: Questions and Answers". National Cancer Institute. Retrieved 2008-08-28. ^ Don X. Nguyen and Joan Massagu, Genetic determinants of cancer metastasis, Nature, 2007. http://www.nature.com/nrg/journal/v8/n5/pdf/nrg2101.pdf 8. ^ Zlotnik A., Burkhardt A. M., Homey B., Homeostatic chemokine receptors and organ-specific metastasis, Nature reviews, 2007 9. ^ Yvette Drabsch, Peter ten Dijke, TGF- Signaling in Breast Cancer Cell Invasion and Bone Metastasis, J Mammary Gland Biol Neoplasia (2011) 16:97108 10. ^ Yoshida BA, Sokoloff MM, Welch DR, Rinker-Schaeffer CW (Nov 2000). "Metastasis-suppressor genes: a review and perspective on an emerging field". J Natl Cancer Inst. 92(21): 1717 30. doi:10.1093/jnci/92.21.1717. PMID 11058615. 11. ^ Matteo Parri, Paola Chiarugi. "Rac and Rho GTPases in cancer cell motility control" 2010 12. ^ Weidner N, Semple JP, Welch WR, Folkman J (Jan 1991). "Tumor angiogenesis and metastasis correlation in invasive breast carcinoma". N Engl J Med. 324 (1): 1 8.doi:10.1056/NEJM199101033240101. PMID 1701519. 13. ^ Gao, D; Nolan, D. J.; Mellick, A. S.; Bambino, K.; McDonnell, K.; Mittal, V. (2008). "Endothelial Progenitor Cells Control the Angiogenic Switch in Mouse Lung Metastasis". Science 319(5860): 195 198. doi:10.1126/science.1150224. PMID 18187653. 14. ^ Nolan, DJ; Ciarrocchi, A.; Mellick, A. S.; Jaggi, J. S.; Bambino, K.; Gupta, S.; Heikamp, E.; McDevitt, M. R. et al. (2007). "Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization". Genes & Development 21 (12): 1546 1558. doi:10.1101/gad.436307. PMC 1891431. PMID 17575055. |displayauthors=suggested (help) 15. ^ Mellick As, Plummer PN et al. (2010). "Using the Transcription Factor Inhibitor of DNA Binding 1 to Selectively Target Endothelial Progenitor Cells Offers Novel Strategies to Inhibit Tumor Angiogenesis and Growth". Cancer Research 70 (18): 72737282. doi:10.1158/0008-5472.CAN-101142. PMC 3058751. PMID 20807818.
16. ^ Jauliac, S; Lpez-Rodriguez, C, Shaw, LM, Brown, LF, Rao, A, Toker, A (2002 Jul). "The role of NFAT transcription factors in integrin-mediated carcinoma invasion.". Nature Cell Biology 4 (7): 540 4. doi:10.1038/ncb816. PMID 12080349. 17. ^ Yoeli-Lerner, M; Yiu, GK, Rabinovitz, I, Erhardt, P, Jauliac, S, Toker, A (2005-11-23). "Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT.". Molecular Cell20 (4): 539 50. doi:10.1016/j.molcel.2005.10.033. PMID 16307918. 18. ^
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15). "NFAT3 transcription factor inhibits breast cancer cell motility by targeting the Lipocalin 2 gene.". Oncogene 29 (15): 2292301. doi:10.1038/onc.2009.499.PMID 20101218. 19. ^ Gaudineau, B; Fougre, M, Guaddachi, F, Lemoine, F, de la Grange, P, Jauliac, S (2012-10-01). "Lipocalin 2 (LCN2), the TNF-like receptor TWEAKR and its ligand TWEAK act downstream of NFAT1 to regulate breast cancer cell invasion.". Journal of cell science 125 (19): 4475 4486.doi:10.1242/jcs.099879. PMID 22767506. 20. ^ List of included entries and references is found on main image page in Commons:Commons:File:Metastasis sites for common cancers.svg#Summary 21. ^ Bacac, M; Stamenkovic, I (February 2008). "Metastatic cancer cell". Annual Review of Pathology 3: 221 47. doi:10.1146/annurev.pathmechdis.3.121806.151523.PMID 18233952. 22. ^ http://www.springerlink.com/content/v8wt2q033u674121/ 23. ^ Robert Weinberg, The Biology of Cancer, cited in Basics: A mutinous group of cells on a greedy, destructive task, by Natalie Angier, New York Times, 3 April 2007 24. ^ Scott, J; Kuhn, P and Anderson, A (July 2012). "Unifying metastasis integrating intravasation, circulation and end-organ colonization". Nature Reviews Cancer 12 (7): 445 446.doi:10.1038/nrc3287. PMID 22912952. 25. ^
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Ramaswamy S, Ross KN, Lander ES, Golub TR (January 2003). "A molecular signature of
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