Targeting Invasion + Metastasis in Cancer Therapy Flashcards
What are the steps in metastasis?
Invasion + infiltration of surrounding normal host tissue with penetration of small lymphatic or vascular channels
Entry of malignant cells into circulation - single cells/small clumps
Survival in circulation
Arrest in capillary beds of distant organs
Penetration of lymphatic or blood vessel walls followed by growth of disseminated tumour cells
Describe travel of metastatic cells via lymphatic systems
Drain through lymphatic system into lymph nodes
Presence of tumour cells in lymph nodes = degree of spread of metastases
What are the vulnerabilities in metastatic cancer?
Cancer cells must disseminate from primary tumour
Has to adapt to new site
Majority of tumour cells that leave primary tumour do NOT survive = against new stresses
Describe journey for metastases
Invasive migration = collective migration + ECM remodelling
Circulation = micro clustering + metabolic adaption
Extravasation = transendothelial migration + capillary disruption
Seeding = perivascular migration
Dormancy entry = invade immune system + growth-suppressive signalling
What is the mechanistic theory?
Determined by pattern of blood flow
What is the “seed + soil” theory?
Provision of environment in which compatible tumour cells can grow
Successful metastases require cancer cells + correct environment to grow
Selective chemotaxis with organ producing soluble attraction factors to tumour cells
So metastasise to specific sites
What are chemokines?
Chemotactic proteins that cause directed migration of cells (leukocytes)
Tumour cells piggyback on this pathway
Chemokines bind to chemokine receptors
Describe importance of chemokine expression
Express CXCR4/CXCL12 natural ligand
Highest in lung, liver, bone marrow, lymph nodes + brain = common sites of metastasis
What happens if you inhibit chemokines?
Prevent cancer cells from moving to metastatic sites
BUT if already had would prevent more movement
= doesn’t kill them just slows down
Describe tumour invasion
Translocation of cells across extracellular matrix barriers
Loss of cell adhesions + attachment to basement membrane
What are the 2 major types of protease?
Serine proteases
Metalloproteinases (MMPs)
Describe MMPs
Central to tumour invasion, angiogenesis + metastasis
Secreted as latent proenzymes
Secreted by stromal cells in response to signals from tumour cells= creates pathway for tumour cells to invade
Activity controlled by TIMPs = inhibitor proteins forming MMP complexes = higher = decrease metastatic potential
How are MMPs involved in steps of tumour invasion?
Help break down nutrients for cells
= release growth factors
Describe 1st generation MMPi
Hydroxamates
Broad spectrum inhibitors
Excellent anti-cancer activity in tumour cells
But joint pain
Needs to be given early
eg. Marimastat
What other opportunities for targeting metastatic cancer?
Targeting supporting cells = just as effective
Target tumour-derived immunosuppressive factors
