The upregulation of cell surface glycoproteins such as CD44s, P-gp, CXCR4 and α4β1 integrin (VLA-4) after EMT results in extensive reorganization of the actin cytoskeleton, directionally persistent cell migration, invasion, and activation of outside-in oncogenic signaling. This leads to detachment from the primary tumor's extracellular matrix, invasion into surrounding tissue, dissemination by the lymphogenic and hematogenic pathways to local lymph nodes, and establishment as metastatic nodules in distant organs.
The upregulation of P-gp and α4β1 integrin (VLA-4) on the cell surface after tumors undergo the epithelial-to-mesenchymal transition (EMT) plays a particularly important role in tumor cell resistance. Primarily considered a drug-efflux transporter, P-gp activates oncogenic signaling through the ERK1/2 and p38 MAPK pathways. Likewise, α4β1 integrin (VLA-4) and CXCR4, primarily considered essential for mediating cell-cell and cell-extracellular matrix adhesion, also activate oncogenic signaling and actin cytoskeletal reorganization through the FAK/Src pathway. Studies have shown that P-gp and α4β1 integrin on the cell-surface are essential for tumor resistance in a number of tumor types.
Tumor suppressor proteins are the cell's naturally-occurring safeguard against uncontrolled cellular proliferation. These proteins are present in normal cells having controlled phosphokinase activity, controlled protein translation, controlled cell cycle progression and controlled cellular proliferation. Much like the effect of the body's immune system, tumor suppressor proteins harness the cell's natural defenses to control the proliferation of cancer. When they are suppressed in tumor cells, regulation of oncogenic signals, cell cycle progression and apoptosis are markedly altered. Dysregulation of PI3k/Akt oncogenic signalling for example prevents the translocation of the FOXO transcription factor to the cell nucleus. This causes downregulation of the naturally-occurring p21waf/cip1 and p27kip1 cyclin-dependent kinase CDK4 inhibitors that regulate the cell cycle in normal cells. Downregulation of tumor suppressors increases as tumor cells metastasize; however, they can be restored.
The inability to control the progression of therapy-resistant metastatic malignant tumors is believed to be responsible for 90% of all cancer related deaths.
These cancer-related deaths are not effectively controlled with conventional cancer chemotherapies, radiotherapy or targeted kinase inhibitors. Tumors treated with conventional targeted, and even immune therapies, become resistant to treatment as the cancer progresses and the tumor cells changes their oncologic properties. Epithelial cells found in primary tumors undergo an epithelial-to-mesenchymal transition (EMT) whereby they are transformed from therapy responsive tumor cells to resistant cells. These resistant cells have an altered genetic makeup, marked changes in the cell surface glycoproteins, and inactivated tumor suppressor proteins.
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