Epithelial-Mesenchymal Transition Concepts

Epithelial-Mesenchymal Transition (EMT)

• EMT is a series of orchestrated events altering cell-cell and cell-extracellular matrix (ECM) interactions.
• Epithelial cells are released from surrounding tissue.
• Cytoskeleton is reorganized for 3D movement in the ECM.
• A new transcriptional program maintains the mesenchymal phenotype.

Cell Types

• Epithelial cells form sheets, typically one cell thick, with cells tightly joined.
• Mesenchymal cells lack a regimented structure and have few intracellular adhesions, allowing for mobility.
• All animals begin as epithelial cells, capable of forming all three germ layers (ectoderm, mesoderm, and endoderm).

Characteristics of Epithelial Cells

• Typically a single cell layer thick.
• Cells abut and join each other.
• Regularly spaced junctions and adhesions between cells.
• Tight adhesion inhibiting movement away from the monolayer.
• Enclose a 3D space within the monolayer, providing structural definition and rigidity.
• Polarized with a negative charge inside the cell membrane compared to the outside.
• Apical and basal surfaces often differ structurally and functionally.
• Adhere to different substrates (ECM).

Characteristics of Mesenchymal Cells

• Lack regimented structure.
• Few tight intracellular adhesions.
• Weak adhesions allowing for mobility.
• Form irregular structures, not uniform in composition or density.
• Extended and elongated shape.

EMT Markers

• Increased abundance: N-cadherin, Vimentin, Fibronectin, Snail1 (Snail), Snail2 (Slug), Twist, Goosecoid, FOXC2, Sox10, MMP-2, MMP-3, MMP9, Integrin vβ6.
• Decreased abundance: E-cadherin, Desmoplakin, Cytokeratin, Occludin.
• Increased activity: ILK, GSK-3B, Rho.
• Accumulate in the nucleus: β-catenin, Smad-2/3, NF-κB, Snail1 (Snail), Snail2 (Slug), Twist.

Biochemical Changes Accompanying EMT

• Expressing Twist transcription factor in MDCK cells induces fibronectin and vimentin.
• Changes include decreases in epithelial markers and increases in mesenchymal markers.

EMT in Development and the Adult

• EMT plays a role in gastrulation and neural crest delamination during development.
• In adults, EMT is involved in wound healing, tissue fibrosis, and cancer metastasis.

Animal Development - I

• Early cleavage forms a ball of cells (blastocyst) with a hollow space (blastocoel).
• The initial structure is an epithelium folded into a ball.
• The second phase involves the formation of a triploblastic embryo.
• Three primary germ layers: ectoderm, mesoderm, and endoderm.
• The process is called gastrulation.

Gastrulation

• Two processes are involved in gastrulation:
  • The epithelial sheet deforms as a unit.
  • A small number of cells at the base or vegetal plate lose contact with neighbors, detach from the basal lamina, and crawl into the blastocoel.

EMT in Tissues

• Epithelium I induces an EMT process in Epithelium II through secreted inducers (intermediary signal molecules).
• The mesenchymal population is recruited and differentiates based on molecular information from the inducing tissue.

EMT and Cancer

• EMT allows benign tumors to infiltrate surrounding tissue and metastasize to distant sites.
• EMT stages are observed in pathological staging of tumors.

What is Metastasis?

• Tumors take years to detect, particularly if growing in extensible space.
• Metastasis occurs when the tumor compromises organ function, prompting symptoms.
• Primary tumors are less lethal than metastasis, which occurs in distant sites.
• Understanding metastasis could greatly extend survival.

What is Metastasis (Further Discussion)?

• Primary tumors rarely cause death, metastasis does in 90% of cases.
• Primary tumor size often predicts metastasis risk.
• Some tumors don't metastasize (skin squamous cell carcinomas, brain glioblastomas), others do frequently (melanoma).
• Some types of tumors exhibit a propensity for specific tissues (breast, prostate to bone) at metastasis.
• Micrometastases at diagnosis correlate with poorer outcomes in breast and colon cancers.
• Organ fibrosis increases risk for aggressive cancer development, such as hepatic cirrhosis and lung fibrosis.

How Do Tumors Spread?

• The process, called the invasion-metastasis cascade, has 6 steps:
  • Primary tumor formation.
  • Localized invasion.
  • Intravasation.
  • Transport through circulation.
  • Arrest in microvessels of various organs.
  • Extravasation (exit from microvessel).
  • Formation of micrometastasis.
  • Colonization and formation of macrometastasis.
• The probability of a single cancer cell completing the metastasis is low.

Are There Metastasis Genes?

• Studies show that various genes are involved with metastasis.
• Some genes are downregulated, others upregulated, and some show expression patterns characteristic of metastasis.
• Genes associated with metastasis correlate with survival prognosis for certain cancers.

EMT in Tumor Progression

• EMT is critical in tumor progression, moving from localized to invasive carcinoma (and eventually to micrometastasis).

Cancer Metastasis Process

• Involves multiple sequential steps following tumor growth and progression.
• Stages can be described as cancer in situ, invasive carcinoma, intravasation, transport in circulation, extravasation, colonization, and micrometastasis formation.

Cancer Metastasis (Molecular Mechanisms)

• EMT involves the loss of adherens junctions (like E-cadherin) and cytoskeletal changes.
• β-catenin's translocation into the nucleus occurs due to EMT, which plays a role in metastasis.

Cancer Metastasis (Other Considerations)

• Stages include detachment of cells, basement membrane degradation, invasion, and intravasation; followed by circulation, extravasation, proliferation, and microenvironmental activation, culminating in the final formation of growing metastases.

This quiz explores the fundamental concepts of Epithelial-Mesenchymal Transition (EMT) and the differences between epithelial and mesenchymal cells. Understand the roles, characteristics, and transformations that cells undergo during EMT. Test your knowledge on the structure and function of these essential cell types.