Lesson 13 Invasion metastasis strategy

• Most cancer deaths are due to metastasis
• Epithelial-to-mesenchymal transition (EMT)


  Drives motility in tumour cells

  
• Carcinomas


  • Epithelial cancers derived from cells of endodermal/ectodermal origin
  • Epithelial cells are typically tightly attached to surrounding cells, non-migratory, polar

  
• EMT in cancer cells

  1. Hypoxia and other stimuli provoke widespread transcriptional changes

  2. Lead to acquisition of invasive characteristics

  3. Gene expression profile and phenotype (looser connections, migratory) resemble mesenchymal cells

  
• Invadapodia


  • Protrusions created by cytoskeletal reorganisation in cancer cells
  • Harbour degradative enzymes that destroy ECM, clearing a path for invading cancer cells

  
• Extracellular matrix (ECM)


  Network of secreted proteins, polysaccharides and glycoproteins that surrounds cells and separates anatomical structure
• Transit of cancer cells within vessels, exit

  1. Cancer cells form transient connections with vessel walls, roll and gradually slow to stop

  2. Use invadapodia to squeeze between endothelial cells lining vessels, degrade ECM and invade into tissue

  
• Most cancer cells do not survive in the vessels due to mechanical force, foreign microenvironment, immune cells
• Factors influencing metastatic sites

  A cancer cell needs to get into the circulation, survive, and exit into a new site that is suitable for its proliferation

  
• Different primary cancers have distinct metastatic patterns

  
• Genetic analysis can model the evolution of cancer within a patient and estimate the timing of each step

  
• Typical diagnosis of pancreatic cancer after metastasis contributes to its lethality
• Particular mutations and epigenetic changes tend to be more common in metastases than primary tumours, and are possible candidates for molecularly-targeted therapies to prevent or eliminate metastases
• ~90% of cancer deaths are caused by metastases
• Preclinical research tends to focus on primary tumours
• Metastatic cancer cells are very adaptable and resilient, and genomically unstable
• There is a dearth of molecular targets for metastases
• Changes in gene expression may drive metastasis – hard to target with drugs
• When/how can we target metastases?

  • Before it happens - eg by preventing primary tumour cells from invading
  • En route - eg killing circulating cancer cells
  • Preventing emergence from dormancy after cancer cells extravasate into secondary site
  • Once metastatic cancer cells start proliferating in the new site
• Targeting invadapodia enzymes has been disappointing so far, with most clinical trials failing
• Non-specific drugs and cancers being too advanced were likely reasons for the failed clinical trials
• A better strategy may be

  Using more selective drugs and treating earlier
• An MMP9 inhibitor suppressed re-growth of primary tumour and lung metastasis, and improved survival, when given prior to resection of the primary tumour in a mouse breast cancer model
• A framework was recently proposed for developing anti-metastasis therapies, with a major goal to test drugs on patients early in the metastasis process
• Patients who could be targeted early in the metastasis process

  • Patients with primary tumours that can't be resected
  • Patients at high risk of metastasis
  • Patients with micrometastases (dormant, or metastases with a balance between cell division/death)
  • Patients with a limited number of small but growing metastases
• Treatment of the primary tumour and standard-of-care adjuvant therapy will remain the initial interventions, followed by potentially lifelong maintenance therapy to prevent the growth of pre-existing (micro)metastases and/or to prevent further spread of metastases
• What we need to develop

  • Biomarkers that identify primary tumours that are most likely to metastasise, and methods to detect them as early as possible (eg before invasion or while only locally invasive)
  • Drugs that are very well tolerated: specific for target molecules with major roles in metastasis and few/no functions in normal cells
• Distinct metastatic patterns

  Unique patterns of spread for different primary cancers