Invasion and Immunity Notes PDF

Invasion and metastasis  Invasion and metastasis are the results of complex interactions between cancer cells and normal stroma and are the major causes of cancer-related morbidity and mortality.  Studies in mice and humans reveal that although millions of cells are released into the...

Invasion and metastasis  Invasion and metastasis are the results of complex interactions between cancer cells and normal stroma and are the major causes of cancer-related morbidity and mortality.  Studies in mice and humans reveal that although millions of cells are released into the circulation each day from a primary tumor, only a few metastases are produced  Invasion occurs in four steps: loosening of cell-cell contacts, degradation of ECM, attachment to novel ECM components, and migration of tumor cells. 1. Cell-cell separation / loosening of cell-cell junctions  Inactivation, alterations, downregulation of epithelial surface protein & intercellular adhesion molecules (e.g. cadherins)  Upregulation of certain mesenchymal markers (e.g., vimentin and smooth muscle actin) 2. Basement membranes and ECM degradation  Benign tumors of the breast, colon, and stomach show little type IV collagenase activity, whereas their malignant counterparts overexpress this enzyme.  Mediated by proteolytic enzymes: matrix metalloproteases and cathepsins.  Release of stored growth factors  Degradation products are also angiogenic and chemotactic  concentrations of metalloproteinase inhibitors are reduced 3. ECM alterations  Fragmented ECM fibers expose different adhesion sites and increases aberrant crosslink and stiffness  Induction of stromal fibroblast to remodel the ECM →also increases stiffness o Löffek et all. Tension in Cancer. Int J Mol Sci. 2016;17(11):1910.  Integrins response changed to avoid apoptosis and stimulate oncogenes  Mechanoreceptors sensing altered environment may promote or block tumor progression: Dombroski et all Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis. Cells. 2021;10(11):2815 4. Locomotion / migration  CCs must attach to the matrix at the leading edge, detach from the matrix at the trailing edge, and contract the actin cytoskeleton to ratchet forward  Need stiffer support to move and chemotactic factors: autocrine and stromal  Vascular Dissemination and Homing of Tumor Cells o Many tumors arrest in the first capillary bed they encounter (lung and liver). o Once in the circulation, tumor cells are vulnerable to destruction (mechanical shear stress, apoptosis stimulated by loss of adhesion, and innate and adaptive immune defenses). o Within the circulation, tumor cells tend to aggregate in clumps. Dr M Hossu Notes 162   adhesions among tumor cells  adhesion between tumor cells and blood cells, particularly platelets o Some tumors show organ tropism: ← expression of adhesion or chemokine receptors whose ligands are expressed by endothelial cells at the metastatic site. o Even when metastases are established, they may grow to only small, clinically insignificant sizes.  May enter dormancy = prolonged survival of micrometastases without progression (well described in melanoma, breast cancer, and prostate cancer). o Metastatic CCs secrete cytokines, growth factors, and ECM molecules that act on the resident stromal cells, which in turn make the metastatic site habitable for CCs  e.g. breast cancer metastases to bone are osteolytic because of the activation of osteoclasts in the metastatic site Evading immunity  Tumor cells can and at least in the initial phases are recognized by the immune system as nonself and destroyed.  Immunosuppressed patients have an increased risk for development of cancer (~200 times the rate in immunocompetent individuals), particularly types caused by oncogenic DNA viruses  Cell proteins that are presented on the cell surface by MHC class I molecules and are recognized by CD8+ CTLs → may become tumor an gens o products of mutated genes, o overexpressed or aberrantly expressed proteins, o tumor antigens produced by oncogenic viruses.  Antitumor activity is mediated by predominantly cell-mediated mechanisms. o T-Cell mediated cytotoxicity:  clear protective role against virus-associated neoplasms (e.g., EBV- and HPV- induced tumors)  the number of tumor-infiltrating CD8+ CTLs correlates with a better prognosis in a variety of cancers  requires Tumor antigen to be presented by APC with costimulators in lymph nodes  most co-stimulators are Danger Associated Molecules (DAMP) released by necrosis o Natural killer cell cytotoxicity  are capable of destroying tumor cells without prior sensitization and thus may provide the first line of defense against tumor cells  preferentially kill cells that possess low levels of MHC class I molecules. o Macrophage-mediated-cytotoxicity  Activated macrophages exhibit cytotoxicity against tumor cells in vitro. Dr M Hossu Notes 163   IFN secreted by T cells and NK cells, is a potent activator of macrophages o some antigens from dead CC may enter CD4 path and lead to Antibody-dependent- cell mediated-cytotoxicity and Complement-mediated cytotoxicity  In immunocompetent patients, tumors may avoid the immune system o selective outgrowth of antigen-negative variants o reduced (but not loss) expression of histocompatibility molecules, o immunosuppression through secreted molecules (factors)  TGF-β: inactivates B cells and Macrophages, blocks cells progress through G1 phase  Decoy molecules: for NK cells receptors  Induction of immunosuppressive regulatory T cells  Switching macrophages to M2  Immune check factors e.g. PD-1 ligands – inactivate CTL Chronic inflammation  Necrosis induces inflammation that becomes chronic and extensive o inflammatory reaction can be so extensive as to cause systemic signs and symptoms: anemia (due to inflammation-induced sequestration of iron and downregulation of erythropoietin production), fatigue, and cachexia.  Infiltrating leukocytes and activated stromal cells have been shown to secrete o growth factors and cytokines that promote angiogenesis, fibroblast proliferation, and collagen deposition o Proteases →degrade ECM = remove one of the barrier to growth o Express adhesion molecules such as integrins that promote direct physical interactions with tumor cells maintaining them “alive”. o stromal cell–cancer cell interactions increase the resistance of cancer cells to chemotherapy Dr M Hossu Notes 164