Landmark Discoveries in Metastasis Research
The Landmark Discovery Project aims to identify and properly annotate discoveries that defined our current understanding of metastasis and drive ongoing research into the treatment of metastatic cancer.
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On the Landmarks of Metastasis Research
While it may be impossible to provide a comprehensive history of metastasis research, we can easily trace the landmark discoveries that provided key insight into the biology and molecular mechanisms of metastasis. Here we outline these landmark discoveries, how they evolved our understanding and sparked new treatments. The current-day understanding is reviewed in "understanding metastasis - for scientists" and a clinical perspective is added in "understanding metastasis - for patients"
We will review landmark discoveries in Metastasis Research. The selected landmarks are primarily based on comprehensive reviews by Dr. Leonard Weiss and Dr. I. Josh Fidler. Historical discoveries for cancer are available through the ACS, Nature and other review publications (pubmed).
On the origin of Cancer
On the Origin of Metastasis
~3000 BCE - Skeletal Metastases in Antiquity. Even in prehistoric times people suffered from metastatic disease. Detailed analysis of ancient skeletal remains have revealed the existence of oncolytic lesions caused by metastatic melanoma.
1727-1850 "Metastasis of Milk". The term "Metastasis" was first applied to all maladies that seem to transpose from their point of origin to another organ with no specific reference or knowledge of cancer. The most prominent example is the "metastasis of milk" which was recorded across several academic publications during the 18th and 19th century including a more recent medical dissertation by Johannis Caroli Friderici Hauff (1827 [Latin]). An interesting compilation is provided in Anomalies and Curiosities of Medicine (Gould and Pyle, 1898) where the metastasis of milk was correctly noted as the product of a metastasized breast cancer in lactating women.
1829 - Definition of "Metastasis". The first recorded definition of "metastasis" in the context of diagnosing and treating cancer was made by the renowned physician (Recamier JC, 1829). See an English summary of the physician and his reference to the diagnosis and treatment of metastasis by Carr and Carr (CBMH/BCHM, 2008)
Understanding the Metastatic Process
1858 - R. Virchow - Tumor Dissemination is determined by mechanical factors
1915 - First murine model of metastasis
1929 - J. Ewing - Metastasis determined by anatomy of channels draining primary tumor
1944 - Role of cellular adhesiveness in metastasis
1952 - Organ specificity of tumor growth after IV Injection of tumor cells
1952 - Transpulmonary passage of tumor cell emboli results in metastases on arterial side
1955 - Cells adapted to ascites growth preexist in partental tumor, have increased malignant phenotype
1962- Enzymatic manipulations of cell surfaces affects metastatic potential
1965 - Radioactive labeling of tumor cells (Chromium) is used to trace disseminating tumor cells
1970 - Metastasis is shown to result from the survival of a few tumor cells
1973 - Human tumors metastasize in thymic-deficient nude mice
1973 - In Vivo selection of tumor cells for enhanced metastatic potential
1975 - The "Metastatic Cascade" proposed for sequential events in cancer dissemination.
1975- Organ specificity of metastasis determined by cell adhesion
1976 - Clonal Evolution of tumor cell populations
1976 - Invasion and metastasis linked to metastatic cells producing proteolytic enzymes
1977 - metastatic heterogeneity of neoplasms
Defining the Biology of Metastasis
1980 - Organ specificity of metastasis shown using ectopic organs
1980 - Regulatory role of the NK cells in tumor metastasis
1980 - Metastatic potential correlated with enzymatic degradation of basement membrane collagen
1981 - Interactions between clonal subpopulations could stabilize metastatic properties; metastatic variants confirm heterogeneity
1982 - First anti-metastasis drug clinical trial (Razoxane)
1982 - Metastasis not due to adaption to a new organ environment, is selective
1982 - Cancer metastases are clonal and originate from a single surviving cell
1982 - Rapid development of metastatic heterogeneity by clonal origin metastases
1982 - Peritoneovenous shunts don't increase ovarian cancer metastasis
1982 - Direct evidence the metastatic process is selective
1984 - Tumor heterogeneity shown for motility and adhesive properties
1984 - Organ-specific metastasis in ovarian carcinoma treated with peritoneovenous shunts
1984 - Metastatic heterogeneity of human tumors shown using immune incompetent mice
1985 - Critical role of macrophages in metastasis
1986- Concept of metastatic inefficiency
1988 - First metastasis suppressor gene
1990 - Utility of bacterial LacZ in detecting micrometastases during tumor progression
1990 - Ability of FDG to detect LN metastases with PET scans
1991 - Relationship between metastasis and angiogenesis in breast cancer
1992 - Role of chemokines in tumor-associated macrophage facilitation of metastasis
1994 - Removal of malignant primary tumor in mice spurs growth of remote tumors or metastases
1997 - Visualization of tumor cell invasion and metastasis using GFP-expresssion
2000 - Gene expression pattern diversity in breast cancer tissue
2001 - Role of cancer stem cells in cancer
2002 - Metastatic potential determined early in tumorigenesis: metastatic molecular signature in primary tumor
2002 - Gene expression profile of primary breast cancer associated with metastasis and poor outcome
2002 - EMT could explain metastatic progression
2002 - Heterogeneity of single disseminated tumor cells in minimal residual cancer
2003 - Breast cancer metastasis ability resides in a few breast cancer stem cells highly resistant to chemotherapy
2003 - Molecular signature associated with breast tumor metastasis to bone
2006 - Role of genetic susceptibility for metastasis
2007 - First metastasis-promoting micro-RNA
2008 - Micro-RNA expression patterns can predict metastatic risk
2008 - Micro-RNAs can suppress metastases