Metastasis is the spread of cancer cells from the original site to distant locations in the body. Cancer cells can spread via blood vessels (hematogenous) as well as lymph vessels in the body.

Epithelial-to-Mesenchymal Transition

The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further activates the transcription factors, such as zinc-finger proteins - Snail, Slug, Twist, and E47. These transcription factors bind to the promoter elements of genes encoding the adherens junction protein E-cadherin and downregulate them. They also recruit histone deacetylase (HDAC) to facilitate chromatin condensation and subsequent transcriptional repression of E-cadherins. Reduced E-cadherin expression results in reduced cell-cell adhesion, modulation of Rho GTPase function, and cell polarity loss, allowing cells to escape tissue constraints and enter the blood circulation.

Once the blood circulating cancer cell reaches a new site, the reverse process converts the mesenchymal-like circulating cells into tumor cells that can adhere to the new environment, leading to secondary tumor formation. This process is called mesenchymal-to-epithelial transition or MET.

Metastasis is a chance event.

The cancer cells that intravasate into blood vessels have a minimal chance to survive and metastasize. The circulating tumor cells (CTC) in the blood and lymph are routinely neutralized by the immune cells (natural killer cells, monocytes/macrophages, and neutrophils). Although the survival rate of CTCs is low, there are several factors that aid cancer cells to survive during circulation. For example, blood platelets shield the CTCs against the binding of natural killer (NK) cells. Platelets also transfer MHC or major histocompatibility complex to CTCs, allowing cancer cells to escape immune surveillance. Cancer cells can also inhibit NK cell activity by downregulating the NKG2D immunoreceptor.

Given the complexity of metastasis and genetic heterogeneity among the tumor cell population, these factors collectively make cancer difficult to cure. Creating therapeutics and treatments that specifically target stages of metastasis may lead to the reduction of the incidence of cancer deaths.