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 ACSNature and other review publications (pubmed). 


On the origin of Cancer

Historical discoveries in tumor biology and the treatment of cancer are available through the ACS and other review publications. 


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.

lactis metastasi1727-1850 "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

1889 - S. Paget - "Seed to Soil" hypothesis for organs with disseminated cancer

1915 - First murine model of metastasis

1929 - J. Ewing - Metastasis determined by anatomy of channels draining primary tumor

Computational modeling is trying to expand upon the theories of metastatic dissmination including recent work using a Markov Chain model [pubmed][Prezi]

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