"The role of αvβ6-dependent TGFβ activation in cancer has been investigated in a number of studies , , , , , that illustrate both the potential and complexity associated with this target. For example, when αvβ6 was blocked with antibodies in the early stages of disease in a transgenic pancreatic cancer mouse model, this accelerated cancer progression when SMAD4 was functional, but not in SMAD4-null animals . "
[Show abstract][Hide abstract] ABSTRACT: The αvβ6 integrin is up-regulated in cancer and wound healing but it is not generally expressed in healthy adult tissue. There is increasing evidence that it has a role in cancer progression and will be a useful target for antibody-directed cancer therapies. We report a novel recombinant diabody antibody fragment that targets specifically αvβ6 and blocks its function. The diabody was engineered with a C-terminal hexahistidine tag (His tag), expressed in Pichia pastoris and purified by IMAC. Surface plasmon resonance (SPR) analysis of the purified diabody showed affinity in the nanomolar range. Pre-treatment of αvβ6-expressing cells with the diabody resulted in a reduction of cell migration and adhesion to LAP, demonstrating biological function-blocking activity. After radio-labeling, using the His-tag for site-specific attachment of (99m)Tc, the diabody retained affinity and targeted specifically to αvβ6-expressing tumors in mice bearing isogenic αvβ6 +/- xenografts. Furthermore, the diabody was specifically internalized into αvβ6-expressing cells, indicating warhead targeting potential. Our results indicate that the new αvβ6 diabody has a range of potential applications in imaging, function blocking or targeted delivery/internalization of therapeutic agents.
PLoS ONE 09/2013; 8(9):e73260. DOI:10.1371/journal.pone.0073260 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Stem cell marker nestin is an intermediate filament protein that plays an important role in cell integrity, migration, and differentiation. Nestin expression occurs in approximately one-third of PDAC cases, and its expression strongly correlates with tumor staging and metastasis. Little is known of the mechanisms by which nestin influences PDAC progression. We showed that nestin overexpression in PDAC cells increased cell motility and drove phenotypic changes associated with the epithelial-mesenchymal transition (EMT) in vitro; conversely, knockdown of endogenous nestin expression reduced the migration rate, and cells reverted to a more epithelial phenotype. In vivo mice studies showed that knockdown of nestin significantly reduced tumor incidence and volume in xenografts. Expression of the nestin protein was associated with Smad4 status in PDAC cells; hence, nestin expression might be regulated by the TGF-β1/Smad4 pathway in PDAC. We examined nestin expression after TGF-β1 treatment in human pancreatic cancer PANC-1 and PANC-1 shSmad4 cells. The TGF-β1/Smad pathway induced nestin protein expression in PDAC cells in a Smad4-dependent manner. Moreover, increased nestin expression caused a positive feedback regulator of TGFβ1 signaling system. We have also found that hypoxia can induce nestin expression in PDAC cells, and the hypoxia-induced expression of nestin is also mediated by TGFβ1 /smad4 pathway. Finally, we demonstrated that two antimicrotubule inhibitors, Cytochalasin D (CD) and Withaferin A (WFA), exhibited anti-nestin activity; these inhibitors might be potential anti-metastatic drugs. Our findings uncovered a novel role of nestin in regulating TGF-β1-induced EMT. Anti-nestin therapeutics is under development as a potential treatment for PDAC metastasis.
Molecular Cancer Research 04/2013; 11(7). DOI:10.1158/1541-7786.MCR-12-0511 · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To study the molecular mechanisms of colorectal cancer liver metastasis.
Cecal wall implantation was performed in nude mice to subclone a highly liver metastatic human colorectal cancer clone (SW1116-M) from SW1116. In vivo and in vitro assays were adopted to confirm the proliferation and metastasis potential. The human tumor metastasis PCR microarrays were used to analyze the differential gene expressions. The results were confirmed further by real-time quantitative PCR.
SW1116-M and SW1116-S5, two human colon cancer cell clones with different metastatic potential, were subcloned from SW1116. In SW1116-M, in vitro invasion, migration and in vivo metastatic potential were higher, and in vitro proliferation rate was lower than SW1116-S5. In tumor metastasis PCR microarray, 24 genes related to cell invading, adhesion, cellular growth and differentiation were found with a twofold difference between SW1116-S5 and SW1116-M. Sixteen of these, including E-cadherins, MTSS1, TRAIL and TRPM1, were up-regulated; eight genes including cathepsin L, EphB2, HGF, MET, MCAM and RORβ were down-regulated.
We have established a highly liver metastatic clone. The subsequent metastasis PCR microarray analysis identified a procedure of cellular differentiation and mesenchymal to epithelial transition (MET) in liver metastasis. The colonization to from macrometastasis is not a switch from cell cycle arrest but a result of cell differentiation and MET.
Journal of Cancer Research and Clinical Oncology 04/2013; 139(7). DOI:10.1007/s00432-013-1424-2 · 3.08 Impact Factor
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