Metastasis, diversity/escape mechanisms, tumor angiogenesis, histological classification of tumors, tumor staging/grading, bone marrow, hematopoiesis

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Department
Biomedical Science
Course
BMS 460
Professor
D.Rao Veeramachaneni
Semester
Fall

Description
25 September Metastasis Three main pathways Through the lymphatics Via blood; hematogenous By seeding surface of body cavities Passage through basement membranes Tumor cells produce receptor proteins, enzymes, and autocrine factors to facilitate attachment to, degradation of basement membrane components and migration away from site of origin Type IV collagenase damages type IV collagen → degradation Primary tumor → metastatic clone evolves → proliferation of the clone and invasion of vessel → transport by circulation → embolization → invasion → new tumor formation at the site of metastasis Tumor-cell invasion and migration: Diversity and escape mechanisms Cancer cells possess a broad spectrum of migration and invasion mechanisms. These include both individual and collective cell-migration strategies. Cancer therapeutics that are designed to target adhesion receptors or proteases have not proven to be effective in slowing tumor progression in clinical trials – this might be due to the fact that cancer cells can modify their migration mechanisms in response to different conditions. Learning more about the cellular and molecular basis of these different migration/invasion programs will help us to understand how cancer cells disseminate and lead to new treatment strategies. Individual or collective tumor-cell migration strategies are determined by different molecular programs From individual to collective movements, increased control of cell-ECM interaction is provided by integrins and matrix-degrading proteases. Cell-cell adhesion through cadherins and other adhesion receptors, as well as cell-cell communication, via gap junctions, are specific characteristics of collective cell behavior. Migration strategy Tumor type Amoeboid Lymphoma Leukemia SCLC Mesenchymal (single cell) Fibrosarcoma Mesenchymal (chains) Glioblastoma Anaplastic tumors Cluster/cohorts Epithelial cancer Melanoma Multicellular strands/sheets Epithelial cancer Vascular tumors Tumor Angiogenesis Tumors secrete angiogenic factors that increase the vascularization and nutrition of an invading tumor. Those angiogenic factors are similar to those producing during normal wound healing. Angiogenesis is initiated at post-capillary venules in response to tissue hypoxia The growing capillary is attracted to an area of higher O2content, ultimately joining with other capillaries to permit circulation. This process is regulated by vascular endothelial growth factor (VEGF) whose production is influenced by the protein hypoxia-inducible factor 1 (HIF-1) The newly formed blood vessels facilitate the dissemination of tumor cells to distant tissues (metastasis) Angiogenesis pathways The major key signaling pathways involved in angiogenesis are the vascular endothelial cell factor (VEGF)-VEGF receptor (VEGF-R) pathway; the Notch receptor pathway; and the Tie (for tyrosine kinase with immunoglobulin-like and EGF-like domains) receptor-angiopoietin (Ang) pathway The VEGF-R and Tie receptors have an intracellular tyrosine kinase domain. Ligand binding to VEGF-R and Tie receptors leads to their dimerization and subsequent autophosphorylation. The phosphorylated receptor interacts with a variety of cytoplasmic signaling molecules leading to angiogenesis involving the proliferation and differentiation of endothelial cells. Activation of the Notch receptor by ligand (D11/Jagged) binding results in the release of the Notch intracellular cell domain (NICD) that translocates into the cell nucleus to regulate gene expression involved in angiogenesis Rebound effect of tumor-starving therapy Based on the importance of VEGF and its receptor in tumor angiogenesis, blocking tumor angiogenesis by suppressing the angiogenic pathways can provide maximal surviving benefits to cancer patients. The monoclonal antibody to VEGF bevacizumab (Avastin) and receptor tyrosin kinase inhibitors (RTKIs) sunitinib and sorafenib have been developed. However, although tumor antiangiogenic targeted drugs inhibit primary tumor growth, they promote tumor invasion and metastasis. The mechanism of tumor hypoxia, caused by oxygen deprivation resulting from blocking tumor angiogenesis, could explain the selective switch of tumor cells into an invasive and metastatic program. Hypoxia-inducible factor-1 (HIF-1) acts as a transcription survival factor that activates genes involved in migration, invasion, and angiogenesis. Hypoxia generated by tumor angiogenesis inhibition triggers pathways that make tumor cells aggressive and metastatic. Clinical Significance: Tumor Angiogenesis and Tumor-starving Therapy All the three signaling pathways, VEGF-R-VEGF, Tie-Ang, and Notch receptor- D11/Jagged, contribute synergistically to the process of angiogenesis. Antiangiogenic drugs exert therapeutic effects by blocking certain specific receptors of the VEGF-VEGF- R pathway, but none can fully block all the components. Thus, angiogenesis signaling can continue through the other signaling pathways. Given the belief that blocking blood supply starves tumors and the importance of VEGF and its receptor and receptor tyrosine kinase inhibitors (RTKIs) in angiogenesis, tumor antiangiogenic therapeutic approaches have been developed to provide cancer patients maximal survival time. Therapy with angiogenesis inhibitors reduce tumor growth but promote invasiveness and metastasis. Tumor-starving therapy Cancer cell hypoxia → hypoxia-inducible factor-1 (HIF-1); a survival transcription factor → angiogenesis, cell migration → metastasis Thalidomide Sedative, sleep aid Children born wi
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