Metastasis, Invasion and Tumor Progression

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Metastasis, Invasion and Tumor Progression
William G. Stetler-Stevenson, MD, Ph.D. Senior
Investigator, LCB, and Vascular Biology Faclty,
NCI
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Goals of Metastasis Research
Understanding molecular mechanisms -understand
disease progression -define new treatment
targets -define new markers of disease
progression
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What is tumor metastasis?
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Metastasis Implications forDiagnosis, Rx and
Prognosis
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What is the origin of metastatic tumor
cells?Can we detect them in theprimary tumor?
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Primary Tumor Heterogeneity
Fidler Kripke, Science 1977
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Tumor Heterogeneity

• Not all cells of the tumor share
• the same metastatic propensity.
• Aggressive subpopulations in the
• primary tumor form metastasis.
• Not all metastasis are derived from the
  same subpopulation.
• Genetic aberrations in metastatic
• lesions will reflect those of primary.
• 4. Dynamic heterogeneity to explain
• similarity of 1 and mets.

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Questions arising from tumor heterogeneity.
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Growth DominanceTheory
Murine SP1 Mammary Carcinoma
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Growth Dominance Theory
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Metastasis with clonal selection
Southern blot ras tagged SP1 cells
NOT GENETIC CONVERGANCE
Dominant clones are homogeneous only in
marker, but are heterogeneous due to continued
genetic instability
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Clonal Selection Model of Progression
The more you play, the more chances to lose.
Mitogenesis versus mutagenesis
Selection involves both genetic and epigenetic
mechanisms.
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Where do metastatic tumor cells come from?
Histopathologic Progression
Normal
Hyperplasia
CIS
Primary Tumor
Mets
Molecular Progression
Chromosome Alteration Gene
5q Mutation or lass FAP
12p Mutation K-RAS
18q Loss DCC
17p Loss p53
Other alterations
DNA Hypomethylation
Normal Epithelium
Fearon Vogelstein, Cell, 1990
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Implications ofMetastasis Theory
Experimental design and interpretation
cDNA microarray, proteomic array, etc.
Metastatic primary vs. metastatic lesions
Non-metastatic primary vs. metastatic primary See
vant Veer et al., Nature 415 530-536, 2002
Premalignant vs. malignant
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Metastatic Cascade
Metastasis formation is complex process that is
the result of a series of sequential,
interdependent steps.
All steps must be successfully completed for
metastasis formation. Each step is rate limiting.
Conceptual framework for the study of the
metastatic process.
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Pathogenesis of Cancer Metastasis
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The Metastatic Process
Individual tumors acquire competence for steps in
a non-sequential (random) order.
Metastasis formation is highly inefficient. Why?
Only 0.01 of circulating tumor cells form foci.
Number of circulating tumor cells correlates
with size and age of primary tumor, but not with
metastasis or clinical outcome
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Where do metastatic cells go?
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Blood flow influence on metastasis
Chambers et al., Nature Cancer Reviews
2563-572,2002
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What factors determine the metastatic site?
Seed-soil hypothesis When a plant goes to seed,
its seeds are carried in all directions but they
can only live and grow on congenial soil.
Stephen Paget, Lancet 1 99-101, 1889
Mechanical hypothesis Pattern of metastatic
spread is determined by mechanical factors and
principal among these is the circulation pattern
between primary tumor and secondary organs.
James Ewing, in Neoplastic Diseases. A Treatise
on Tumors, pp77-89, 1928.
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Metastasis and Cell Migration
Local invasion at primary tumor site.
Tumor cell entry to lymphatic and vascular
compartment.
Tumor cell exit from lymphatic and vascular
compartment.
Host cell invasion of tumor compartment.
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Ameboid vs. Mesenchymal
Friedl an Wolf, Nature Reviews Cancer 3362-374,
2003
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Migratory Phenotypes
Friedl an Wolf, Nature Reviews Cancer 3362-374,
2003
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Progression Migration
Friedl an Wolf, Nature Reviews Cancer 3362-374,
2003