20.6: Metastasis

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 activate 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.

Metastasis is a multi-step process, where the tumor cells overcome several challenges to spread from the primary site to form secondary tumors in the body. As few as one  in a million cells manage to achieve metastasis.

Normal cells are confined to their tissue of origin by cell-cell adhesion and the basement membrane, which is a physical barrier present between tissues. Cancer cells overcome the tissue constraints by a process called epithelial to mesenchymal transition or EMT.

This transition activates two transcription factors, Snail and Twist, which promote the expression of genes involved in cell migration and down-regulate the cell-adhesion factors such as E-cadherin.

Transformed cells then penetrate the basement membrane by extending invadopodia, the actin-rich protrusions. Invadopodia secrete proteases, which degrade the basement membrane.

Once they are freed from the tissue constraints, the transformed cells reach the blood vessel by modifying the extracellular matrix.

Tumor cells then breakdown the basement membrane of the vessel and squeeze through the epithelial cells’ tight junctions to enter the blood circulation by a process called intravasation.

The majority of the circulating tumor cells or CTCs die during circulation due to lack of cell-cell adhesion and also by immune surveillance. Some CTCs secrete substances like thrombin, and cancer procoagulant, to stimulate platelet coating around them. This helps CTCs escape the shear  stress during circulation and also to escape immune surveillance.

In addition, certain CTCs express survivin proteins that suppress the action of cytotoxic natural killer cells.

Initially, the CTCs adhere weakly to the endothelial cells via adhesion molecules and roll along the vessel lining until they form a firm attachment to the vessel. Then they squeeze through the vessel’s endothelial lining, digest the basement membrane and enter a new, distant tissue by a process called extravasation.

Once in the new site, the tumor cells adapt to the foreign tissue environment to form microcolonies and eventually proliferate to form macroscopic secondary tumors.

• Metastasis – Spread of cancer cells from original site to other body parts.
• Epithelial-to-Mesenchymal Transition (EMT) – Process aiding in cancer metastasis, wound healing, and embryogenesis.
• Receptor Tyrosine Kinase (RTK) ligands - Induce EMT by activating transcription factors.
• E-cadherin – Adherens junction protein downregulated in EMT leading to reduced cell-cell adhesion.
• Mesenchymal-to-Epithelial Transition (MET) - Opposite of EMT, converting circulating cells back into tumor cells.

• Define Metastasis – Describe the process of cancer spread (e.g., metastasis).
• Contrast EMT vs MET – Explain the role of these processes in cancer metastasis (e.g., EMT and MET).
• Explore RTK ligands – Describe their role and how they trigger EMT (e.g., RTK ligands).
• Explain E-cadherin – Its downregulation in EMT and its effect on cell adhesion.
• Apply in Context – Discuss relevance of MET and EMT transitions in creation of cancer treatment protocols.

• What is Metastasis and how does the Epithelial-to-Mesenchymal Transition assist it?
• How does receptor tyrosine kinase (RTK) ligands induce the Epithelial-to-Mesenchymal transition?
• What role does E-cadherin play in the process of cancer metastasis?

• Students – Understand How the concept of metastasis supports student learning about cancer biology.
• Educators – Provides a clear framework for teaching about cancer metastasis and associated concepts.
• Researchers – Relevance of studying metastasis and EMT for developing cancer treatments.
• Sciences Enthusiasts – Offer insights into cancer biology, providing broader interest and stimulating curiosity.