Basic Principles of Cancer Pathophysiology
Most common and deadly cancers include lung, breast, prostate, and colorectal.
Microenvironment of the metastatic tumor can modify its biology and response to drugs.
Mechanism of Metastasis
(Raymond removed an image describing the mechanism of metastasis: primary tumor, proliferation & angiogenesis, detachment & invasion of the circulation, transport to a distant site, arrest, adherence to and extravasation through vessel wall, establishment of a microenvironment, and repeat.)
Formation of the primary tumor
Tumor cells invade stroma and communicate with stromal cells. Tumor is avascular.
Both tumor and host cells promote metastasis by activating growth factor pathways, allowing invasion, and promoting angiogenesis.
Tumors inhibit metastasis by being antigenic, by cohesion (via e-cadherin), and by inhibiting angiogenesis.
Host cells inhibit metastasis by putting up tissue barriers, sending immune cells to kill tumor, and inhibiting angiogenesis.
Progressive growth and angiogenesis
Angiogenesis occurs when tumors secrete angiogenic agents such as VEGF and FGF, and by their recruiting lymphocytes and macrophages to secrete these agents as well. The capillary BM degrades locally, creating a vascular deformity and allowing new endothelial modeling.
The tumor or macrophages may also secrete anti-angiogenesis agents such as angiostatin, endostatin, and thrombospondin.
Invasion
Tumor cells invade host stroma using enzymes, then enter blood stream or lymphatics (which have thinner walls).
The host reaction to this invasion is a fibrous ECM called the “desmoplastic response.”
Transport of cancer cells
Single cells or aggregates detach. Blood stream is very hostile to cancer cells, so aggregates survive better, and become trapped in microvasculature downstream. Adhere to endothelial cells or even the BM and invade distant tissue.
Interestingly, presence of cancer cells in circulating blood and bone marrow is not associated with worse clinical outcome!
Cancer cells deposit based on circulation mechanics and chemokines in target tissue. GI cancers go to liver, breast cancers to lungs. Cancer then has to set up new microenvironment – this is an inefficient step. Growth factors supporting new cancer include TGF-β and IGF1.
Remember, tumor cells express chemokine receptors complementary to target organ chemokines. Therefore, chemokines influence patterns of spread between organs.
Dormancy
One model for relapse is that dormancy has persistent tiny pre-angiogenic metastases, in which tumor cell growth is balanced by apoptosis.
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