A detailed compilation of the current scientific evidence on metastasis and its mechanisms.

1. Dr. KRITHIKA A RAMASWAMY
BNYS INTERN
S-VYASA UNIVERSITY
Metastasis

2. What is Cancer?
Grows independently
Uncontrollably
In an uncoordinated manner
At the expense of normal tissues
Monoclonal cell line that:

3. Invasion
1. Angiogenesis
2. Loss of homotypic cell adhesions
3. Adhesion of tumor cells to basement
membrane
4. Proteolysis
Tiny crablike feet penetrating the
margin and infiltrating adjacent
structures.

4. Metastasis
Seeding within
body cavities
Lymphatic
spread
Hematogenous
spread
Robbins and Cotran. (2018). Basic Pathology (10th ed). Elsevier USA. file:///C:/Users/Krithika A Ramaswamy/Downloads/Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C.
Aster (z-lib.org).pdf
Metastasis is defined as the spread of a cancer from one organ, or “primary site”,
to another non-connected “secondary site”.

5. Clinical Importance
Metastasis accounts for 90% of cancer-related deaths in patients with palpable clinical traits, subjective
to the cancer type.
Zeeshan, R., & Mutahir, Z. (2017). Cancer metastasis - Tricks of the trade. In Bosnian Journal of Basic Medical Sciences (Vol. 17, Issue 3, pp. 172–182). Association of Basic Medical
Sciences of FBIH. https://doi.org/10.17305/bjbms.2017.1908

6. Initiation
1
Hostile micro-
environment
2
Triggers
stress
responses
3
Hypervariability
of normal
programmes
regulating cell
migration,
nutrient uptake,
and tissue
organization
4
More
successful
mutations
are
preserved
over time
Nikolaou, S., & Machesky, L. M. (2020). The stressful tumour environment drives plasticity of cell migration programmes, contributing to metastasis. In Journal of Pathology (Vol. 250, Issue
5, pp. 612–623). John Wiley and Sons Ltd. https://doi.org/10.1002/path.5395

7. Angiogenesis
•The VEGF/VEGFR signaling pathway is upregulated in many types of
cancers, contributing to uncontrolled angiogenesis and metastatic
spreading.
•The new vasculature originated by tumor-released VEGF-A is usually
structurally and functionally abnormal.
•High plasma levels of VEGF-A in cancer patients were found to correlate
with a reduced maturation of dendritic cells (DCs), causing impaired
differentiation of effector T and natural killer (NK) cells.
Ceci, C., Atzori, M. G., Lacal, P. M., & Graziani, G. (2020). Role of VEGFs/VEGFR-1 signaling and its inhibition in modulating tumor invasion: Experimental evidence in different metastatic
cancer models. In International Journal of Molecular Sciences (Vol. 21, Issue 4). MDPI AG. https://doi.org/10.3390/ijms21041388

8. The Epithelial-Mesenchymal
Transition
•Normally employed during embryogenesis and, in adults, the healing of epithelial tissues
•Associated with the loss of epithelial properties and the acquisition of certain
mesenchymal features in their stead.
•EMT confers on neoplastic cells, properties that are critical to invasion and metastatic
dissemination, notably increased motility, invasiveness and the ability to degrade
components of the extracellular matrix (ECM)
•Co-ordinated by EMT-inducing transcription factors (EMT-TFs), notably Snail, Slug,
Twist and Zeb1
•Not binary, “partial EMT”
Lambert, A. W., Pattabiraman, D. R., & Weinberg, R. A. (2017). Emerging Biological Principles of Metastasis. In Cell (Vol. 168, Issue 4, pp. 670–691). Cell Press.
https://doi.org/10.1016/j.cell.2016.11.037

9. Metabolism and cancer
•Fat metabolism
•Oxygen demand
hypoxia-inducible transcription factor 1 alpha (HIF1-α)
Fulfills
increased
energy
demand
Substrates
for FA
oxidation
Building
blocks for
signalling
metabolites
Upregulates
fatty acid
synthesis
Pascual, G., Domínguez, D., & Benitah, S. A. (2018). The contributions of cancer cell metabolism to metastasis. In DMM Disease Models and Mechanisms (Vol. 11, Issue 8). Company of
Biologists Ltd. https://doi.org/10.1242/dmm.032920

10. Formation of a metabolic
microenvironment for tumor metastasis
Supports tumor
metastasis
Glucose uptake,
lactate
production and
oxygen
consumption
Switch from
oxidative
phosphorylation
to aerobic
glycolysis
Reprogram
metabolism in
surrounding
fibroblasts
Cancer cells
• Glucose metabolism
Kogure, A., Naito, Y., Yamamoto, Y., Yashiro, M., Kiyono, T., Yanagihara, K., Hirakawa, K., & Ochiya, T. (2020). Cancer cells with high-metastatic potential promote a glycolytic shift in
activated fibroblasts. PLoS ONE, 15(6 June). https://doi.org/10.1371/journal.pone.0234613
•Influences derived from lifestyles, such as our diet or other daily habits, exert a strong influence on tumor
progression

11. The Physics of Metastasis
•Cancer cells are softer than normal cells.
•Tumor cells undergo dramatic shape changes, driven by cytoskeletal remodeling,
that enable them to penetrate endothelial cell-cell junctions.
•The mechanical properties of cancer cells might dynamically change during the
metastatic process to successfully survive the harsh and changing environment
of blood vessels, lymphatic vessels and the stromal space.
Wirtz, D., Konstantopoulos, K., & Searson, P. C. (2011). The physics of cancer: The role of physical interactions and mechanical forces in metastasis. In Nature Reviews Cancer (Vol.
11, Issue 7, pp. 512–522). NIH Public Access. https://doi.org/10.1038/nrc3080

12. CTC
•The survival rate of the circulating tumor cells (CTCs) is around 0.2% (1)
•In the past 15 years, CTC isolation technologies have developed.
Positive isolation
Negative isolation
•CTC molecular analysis
CTC clusters have 23 to 50 times greater metastatic potential than single cells
Metastasis-initiating cells (MICs) have been proposed to represent a subpopulation
of CTCs found in circulation
Systematic drug-sensitivity testing in the clinic from freshly isolated CTCs (2)
1. Zeeshan, R., & Mutahir, Z. (2017). Cancer metastasis - Tricks of the trade. In Bosnian Journal of Basic Medical Sciences (Vol. 17, Issue 3, pp. 172–182). Association of Basic Medical
Sciences of FBIH. https://doi.org/10.17305/bjbms.2017.1908
2. Castro-Giner, F., & Aceto, N. (2020). Tracking cancer progression: From circulating tumor cells to metastasis. In Genome Medicine (Vol. 12, Issue 1). BioMed Central Ltd.
https://doi.org/10.1186/s13073-020-00728-3

13. Metastatic Seeding
•Paget’s “seed and soil” hypothesis
Lung
Liver
Bone marrow
•The “mechanical” hypothesis
Mechanotransduction/ adhesion
Physical occlusion
Montagner, M., & Dupont, S. (2020). Mechanical Forces as Determinants of Disseminated Metastatic Cell Fate. Cells, 9(1), 250. https://doi.org/10.3390/cells9010250

14. Concomitant Immunity
Primary Tumour
Suppress immunity
Immune suppressive
stroma
(CD4+ CD25+ Treg)
Activate Immune
system
Tumour cells acquire
high levels of
mutations and
alterations
Janssen, L. M. E., Ramsay, E. E., Logsdon, C. D., & Overwijk, W. W. (2017). The immune system in cancer metastasis: Friend or foe? In Journal for ImmunoTherapy of Cancer (Vol. 5, Issue
1). BioMed Central Ltd. https://doi.org/10.1186/s40425-017-0283-9

15. Chronology
Linear Progression Parallel Progression
Tumorigenesis
Metastatic seeding
Tumorigenesis Metastatic seeding
Hu, Z., & Curtis, C. (2020). Looking backward in time to define the chronology of metastasis. In Nature Communications (Vol. 11, Issue 1). Nature Research.
https://doi.org/10.1038/s41467-020-16995-y

16. Thank You