Cancers are thought to start in one location and spread to other sites by a process called metastasis. This spread of cancer to multiple sites is what typically leads to death. The primary tumor is the nursery for the production of cells that are able to leave the tumor, migrate to blood vessels and infiltrate other tissues. Thus lung cancers typically kill smokers by terminal brain tumors.
The primary tumors appear to have a controlling influence over subordinate satellite tumors and can keep the subordinates quiescent or turn them into aggressively growing secondary tumors. Production of osteopontin, a cytokine-like hormone associated with bone production, by primary tumors can stimulate quiescent metastasized cells into proliferation.
Recent reports show that a primary human breast tumor established in a mouse can stimulate proliferation of quiescent colon cancer cells. Osteopontin produced by the primary tumor stimulates invasiveness and growth of the secondary cancer cells and also recruits bone marrow stem cells that further enhance proliferation.
Other studies have shown that inflammation is required for cancer and osteopontin activates NFkB, the inflammation transcription factor. It is interesting that the presence of the heparan sulfate proteoglycan, syndecan 4, blocks this process.
Human osteopontin has very strong heparin-binding domains and internalization signals (blue R and K) that suggest that this protein would rapidly bind to surface heparan sulfate proteoglycans and be internalized. The adjacent pairs of basic amino acids also suggest that osteopontin my be transported to and into nuclei, and have transcription modifying capability.
Osteopontin is activated by the serum protease thrombin, also known for activating fibrinogen into fibrin to form clots. The cleavage site (green) for thrombin on osteopontin is just to the left of a strong heparin-binding domain to which the heparin of syndecan 4 binds. Thus heparin binding to osteopontin blocks access to thrombin and leaves osteopontin in an inactive form. Also notice that the upper half, N terminal, of osteopontin is dominated by acidic, negatively charged amino acids, D and E, whereas all of the positively charged, heparin-binding domains are on the other half that activates inflammation.
These studies highlight the roles played by inflammation and heparin in cancer. Anti-inflammatory diets and lifestyles enhance heparin production and reduce the potential for cancer. This also suggests that heparin therapies should be explored for use in cancer prevention and treatment.