Tumor migration

Tumor migration, invasion, extravasation, circulation with blood, interaction with endothelium, and establishment of a microenvironment are aU dependent on specific adhesive interactions of tumor cells with other cells and components of the extracellular matrix. Some of these important interactions are mediated by selectins and their ligands—sialyl Lewis and sialyl Lewis [122-124]. Selectins are adhesion receptors expressed on activated platelets (P-selectin), leukocytes (L-selectin), and endothelial cells (E-selectin) [125]. Unlike normal healthy endothelial cells which do not express E-selectin, primary tumors in patients secrete inflammatory cytokines such as TNF a, which induce E-selectin on endothelial cells [126]. Sialyl Lewis and sialyl Lewis are ligands for E-selectin, and therefore responsible for the adhesion of human tumor cells to endothelium [ 127]. With platelets and leukocytes, tumor cells can form multicellular complexes (via P-selectin) and then settle down in the microvasculature (via L-selectin) of distant organs and eventually extravasate and establish metastatic colonies [128] (Fig. lc,d). 

Transforming growth factor-beta (TGF- 3) proteins are multifunctional morphogens that control cell proliferation, differentiation and apoptosis, as well as cell migration and immune surveillance. TGF-(3 acts as a tumor suppressor, but can also act as a tumor promoter in... 

Migrastatin (192) (Scheme 37) is a novel macrolide natural product that displays an inhibitory effect on the migration of human tumor cells. After an RCM-based synthesis of the 14-membered macrolide core of 192 [94], Danishefsky also achieved the first total synthesis of the natural compound [95], using the fully functionalized tetraene 191 as the metathesis precursor. Under the conditions shown in Scheme 37, the ring-closing step proceeded (E)-selectively with exclusive participation of the two terminal double bonds in 191, delivering only the ( , ,Z)-trienyl arrangement present in 192. 

Hyaluronic acid may be important in permitting tumor cells to migrate through the EGM. Tumor cells can induce fibroblasts to synthesize greatly increased amounts of this GAG, thereby perhaps facifitating their own spread. Some mmor cells have less heparan sulfate at their surfaces, and this may play a role in the lack of adhesiveness that these cells display. 

Metastasis The migration of cancer cells from the original tumor site through the blood and lymph vessels to produce cancers in other tissues. 

Szekanecz Z, Shah MR, Harlow LA, Pearce WH, Koch AE. Interleukin-8 and tumor necrosis factor-alpha are involved in human aortic endothelial cell migration. The possible role of these cytokines in human aortic aneurysmal blood vessel growth. Pathobiology 1994 62(3) 134-139. 

Marchesi F, Monti P, Leone BE, et al. Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4. Cancer Res 2004 64 8420-8427. 

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