Microenvironmental regulation of metastasis

จาก TSWiki

Introduction

Once cancer cells leave their primary sites, they need to survive in circulation, arrive the target organ (seeding), extravasate into parenchyma, and growth persistently. These steps are, however, inefficient and rate-limiting. Cancer cells trying to enter these sites will mostly be senescent or apoptotic, preventing the spread of the majority of circulating cells. This means that seeding can occur at multiple organs, but metastatic sites can be in only a few. Also, evidences show that metastatic cells can be dormant for years, while seeding can occur many years before the diagnosis of the primary tumor. Another mechanism at play is angiogenic dormancy, in which the balance between proliferation and apoptosis keep the micrometastasis from progressing. It is clear that the microenvironment somehow suppresses the malignancy, and only when it is perturbed may these cells be re-activated and form clinically relevant mets. Many studies suggest a link between large tumor size and metastasis-enhancing gene signatures. Tumor grade is also another main predictor of mets. Possibly, the metastatic reseeding to primary tumors may be responsible, although the mechanism is still elusive. The success in metastasis formation depends on the (cumulative) ability to appropriate distinct microenvironments.

Tumor-Stroma interactions at primary site

  • Cells in normal tissues have positional identity
    • Location is defined
    • Numbers are constrained
  • Cancers lost these constraints, but still have (dynamic) interactions with stromal cells and ECM
    • Evolve with tumor, via recruitment of BMDCs (Bone MArrow-Derived Cells)

Normal tissue homeostasis

  • Tightly controlled balance of proliferation and apoptosis -- via intracellular communication
  • ECM
    • Physical scaffold
    • Facilitate interactions between cell types
    • Provide survival and differentiation signals
  • Ensure stable tissue structure
    • Mediated by tight junction proteins and cell adhesion molecules (<math>\beta</math>1 integrins and epithelial (E)-cadherin)

Mints showed that microenvironment of mouse blastocyst suppresses tumorigenicity of tetracarcinoma cells, and also stably reprogrames them --> normal chimeric mice

  • Embryonic microenvironment has the ability to reprogram various cancer cells to a less aggressive phenotype
  • Stromal fibroblasts were shown to modulate malignant progression of transformed epithelial cells
    • e.g. prevent growth of initiated prostatic epithelial cells, and reverse malignancy of neoplastic epithelial cells
  • Protective constrains of microenvironment are perturbed by...
    • Chronic inflammation
    • Local microenvironment shifts to growth-promoting state

Recruitment of stromal cells

  • Endothelial cells
  • Pericytes
  • Fibroblasts
  • BMDCs (Macrophages, neutrophils, mast cells, myeloid cell-derived suppressor cells (MDSCs), MSCs)

Chronic inflammation and BMDC recruitment

  • Leukocytes in tumor were thought to be the results of failed attempt to kill cancer cells
  • Tumors usually escape immunity and also modify certain inflammatory cell types to promote tumors instead!!!
  • Infiltrated immune cells may not be associated with detection of antigens, but may be with tissue disruption caused by inflammatory agents/ response to tumor growth
  • Initial inflammation is not resolved