Introduction to Metastasis

Introduction to Metastasis

• Metastasis allows cancer cells to spread from their primary site to distant tissues and organs
• Metastasis is a major cause of cancer-related morbidity and mortality
• Understanding the molecular mechanisms of metastasis can help in developing strategies for early detection, treatment, and prevention of metastatic disease

Mechanisms of Metastasis

• Metastasis involves complex interactions between cancer cells, the surrounding tissue microenvironment, and host cells

Local Invasion

• Cancer cells invade surrounding normal tissues, the first step in metastasis
• Involves the breakdown of the extracellular matrix (ECM) and changes in cell-cell adhesion

Key Molecular Players:

• Matrix Metalloproteinases (MMPs) degrade ECM components, enabling cancer cells to invade local tissues
• E-cadherin downregulation leads to loss of cell-cell adhesion and increased invasiveness
• Integrins mediate attachment to ECM components, which impacts cell migration

Intravasation

• Cancer cells have to enter the bloodstream or lymphatic vessels to spread to distant sites
• This step involves cancer cells invading the endothelial lining of blood or lymphatic vessels

Molecular Mechanisms:

• Cancer cells encourage new blood vessel formation (angiogenesis)
• The tumor microenvironment supports intravasation via secretion of pro-inflammatory cytokines and growth factors like VEGF and TNF-α

Circulation

• Cancer cells are carried via the bloodstream or lymphatics to distant organs
• Many circulating cancer cells are destroyed by the immune system or mechanical shear stress

Key Concepts:

• Circulating Tumor Cells (CTCs) presence means that cancer cells detached from the primary tumor and entered the blood
• Platelet Aggregation involves CTCs binding to platelets, protecting them from immune surveillance and aiding their survival in circulation

Extravasation

• Cancer cells exit the bloodstream or lymphatics to invade distant tissues or organs
• Cancer cells interact with endothelial cells in distant vessels and then invade the surrounding tissue

Molecular Mechanisms:

• Adhesion Molecules; Integrins and selectins help cancer cells adhere to the endothelium for extravasation
• Cytokines and Growth Factors; Tumor-derived cytokines like CXCL12 increase endothelial cell permeability, promoting extravasation

Colonization

• Cancer cells adapt to and grow in the new environment after extravasation in a secondary site

Key Molecular Mechanisms:

• Tissue-Specific Homing; Some cancers target specific organs, this homing is mediated by interactions between tumor cell surface receptors and ligands in specific organs
• Pre-metastatic Niche; The primary tumor releases factors (exosomes, cytokines) that create a favorable environment for metastatic cell growth

Molecular and Genetic Changes in Metastasis

Genetic Alterations

• Oncogene Activation; Oncogenes like RAS, MYC, and HER2 boost cell survival, proliferation, and migration
• Tumor Suppressor Gene Loss; Loss of tumor suppressors like p53, RB1, and E-cadherin increases the metastatic potential of cancer cells
• Mutations in p53 impair the cell's ability to undergo apoptosis, allowing abnormal cells to survive and invade surrounding tissues

Epigenetic Changes

• DNA Methylation; Hypermethylation of tumor suppressor genes silences their expression
• Histone Modifications; Alterations in histone proteins change chromatin structure and gene expression

MicroRNA Regulation

• MicroRNAs (miRNAs) regulate gene expression, and in cancer they promote metastasis
• An example is miR-10b, which is overexpressed in metastatic cancers and regulates genes involved in cell migration and invasion

Epithelial-to-Mesenchymal Transition (EMT)

• EMT is when epithelial cells lose cell polarity and adhesion properties but gain migratory and invasive characteristics

Molecular Players:

• ZEB1/2 and Twist transcription factors regulate EMT and reducing epithelial markers like E-cadherin
• Fibronectin and Vimentin mesenchymal markers are upregulated during EMT

Tumor Microenvironment and Metastasis

• The tumor microenvironment (TME) involves tumor cells, stromal cells (fibroblasts, endothelial cells), immune cells, and ECM components

Angiogenesis

• Metastatic tumors require blood vessels to provide nutrients and facilitate spread
• Vascular Endothelial Growth Factor (VEGF) drives angiogenesis
• Tumor-Associated Macrophages (TAMs) support angiogenesis and invasion by secreting pro-inflammatory cytokines

Immune Evasion

• Metastatic cells develop mechanisms to evade immune detection
• PD-L1 expression on cancer cells interacts with PD-1 on T-cells, inhibiting the immune response
• Tumor-Associated Macrophages (TAMs) polarized to M2 phenotype support tumor growth and metastasis

Extracellular Matrix (ECM) Remodeling

• The ECM is a physical barrier to tumor invasion, the metastatic produce enzymes such as MMPs and cathepsins to degrade the ECM, for tissue invasion
• Cancer-associated fibroblasts (CAFs) in the TME secrete TGF-β and IL-6, further support ECM remodeling and metastatic progression

Clinical Implications of Metastasis

Clinical Features of Metastasis:

• Lymphatic Metastasis; Involves regional lymph nodes and is common in breast cancer and melanoma
• Hematogenous Metastasis; Spread through the blood to organs and is common in sarcomas, renal cell carcinoma, and colorectal cancer

Metastatic Site-Specific Homing

• Bone Metastasis; Common in breast, prostate, and lung cancers, which is caused by cancer cells secreting factors such as RANKL, leads to bone resorption
• Liver Metastasis; Colon and pancreatic cancers metastasize to the liver due to the organ's vascular structure

Metastatic Marker Detection

• Circulating Tumor Cells (CTCs); Detection of CTCs in blood is a diagnostic tool for metastatic spread
• Exosomes; Cancer cells secrete small vesicles carry metastasis-related proteins, RNA, and microRNA

Therapeutic Targeting of Metastasis

Inhibition of EMT

• Targeting EMT regulators such as Twist and ZEB1/2 can inhibit metastasis

Targeting Tumor Angiogenesis

• Inhibitors of VEGF (e.g., Bevacizumab) reduce blood vessel formation in tumors, inhibiting metastasis

Immunotherapy

• Immunotherapies targeting immune checkpoints such as PD-1/PD-L1 may prevent immune evasion by metastatic tumor cells

Nanomedicine

• Nanoparticles are explored for targeted drug delivery to metastatic tumors, minimizes side effects and improving therapeutic efficacy