Early stage cancer cell invasion: signaling, biomarkers and therapeutic targeting

Abstract

The process of primary cancer invasion of distant organs is multifactorial and multistep. Successful therapeutic management of invasive cancers remains hampered by the multitude of overlapping signaling pathways that initiate and drive cancer cell migration. A crucial early event by which cancer cells switch from localized to invasive states is initiated by the acquisition of autonomous motile properties; a process driven by dynamic assemblies and disassemblies of multiple focal adhesion, cytoskeleton and motor proteins. Several of the protein complexes involved are tightly regulated through posttranslational modifications and intermolecular collisions with partners that occur in a time- and space-dependent manner. These concerted mechanisms are essential for the regulation of cell shape, cell polarity, and cell motility and migration in response to chemotactic signals. This review summarizes the current knowledge in the field and potential clinical implications for molecular pathology and cancer therapeutics. It is not meant to be comprehensive; aspects related to basic signaling are not dealt with extensively in this review. However, the reader is referred to excellent reviews that provide coverage of these topics.

KLF4 inhibition of lung cancer cell invasion by suppression of SPARC expression

“…To further investigate the mechanisms underlying KLF4-induced anti-invasion activity, we analyzed the expression of various genes that were reported to play roles in cancer cell invasion, 32,33 including MMP1 , MMP9 , SPARC , TERT , PKLR , IL3RA , IGF1 , VEGFA , RHOC , TGFB1 , PLAU , and VCAM1 (28–34). For this purpose, we isolated total RNA and determined mRNA levels in these genes in parental, vector-transfected, and KLF4-transfected H322 and A549 cells by using real-time PCR.…”

“…1 μg of RNA from each sample was reverse transcribed in a 20 μL reaction volume with use of the Taqman reverse transcription reagents (Applied Biosystems, Foster City, CA) according to the manufacturer’s instructions. The cDNAs were diluted and quantified for expression of above given gene using real-time PCR (SYBR Green I) performed by Ziren Research LLC (Irvine, CA), with use of a single standard for getting the absolute ratio of each target and reference gene expressions, the procedure was performed as previously described 51, 33. The primer sequences for KLF4 , SPARC , MMP1 , MMP9 , TERT , PKLR , IL3RA , VEGFA , RHOC , TGFB1 , IGF1 , VCAM1 , PLAU , ADAMTS1 , and ACTB (β-actin used as internal reference gene) are available from Ziren Research LLC (www.zirenresearch.com) upon request.…”

Choosing the right path: enhancement of biologically relevant sets of genes or proteins using pathway structure

“…In contrast, the adherens junction, regulation of actin cytoskeleton, cell adhesion molecules, and focal adhesion pathways are significant using SEPEA_NT3 , but are not considered significant using the SEPEA_NT3 * method ( P ≤ 0.05). These pathways, in particular the focal and cell adhesion pathways, all deal with cell to cell communication and are thought to be key modulators of progression and invasion of malignant phenotypic characteristics [ 50 ]. In fact, several novel cancer chemotherapy drugs are being designed to specifically act on the focal adhesion pathway and many standard chemotherapy drugs modulate this pathway in conjunction with their primary mode of action [ 51 ].…”

Carcinoma Metastasis – An Approach to Models

“…Reduced expression or delocalization of such adhesion is thought to play a role in the depolarization of epithelial cells, such as suppression of epithelial cadherin (adhesive link), occludin and claudine (tight junctions) and desmoplakin (desmosomes). Mechanisms involved in malignant cell adhesion have recently been reviewed [25][26][27][28][29]. In summary, the reorientation of depolarized epithelial cells is made possible by repeated detachment and attachment, thereby pointing out a central role for adhesion molecules as the main cellular polarity facilitators.…”