Ductal Cancer Cells Research Articles

Retinoid signaling directs secondary lineage selection in pancreatic organogenesis

Background/Purpose: Retinoid signaling plays an important role in many differentiation pathways. Retinoid signaling has been implicated in the induction of differentiation by pancreatic ductal cancer cell lines and in patients with pancreatic cancer. The authors wished to better understand the role of retinoid signaling in pancreatic development. Methods: Embryonic pancreas was harvested from mice at serial gestational ages and immunohistochemical analysis was performed for retinoic acid receptors (RAR-α, RAR-β, RAR-γ), and retinoid X receptors (RXR-α, RXR-β, and RXR-γ). Also, early embryonic pancreases were cultured for 7 days with exogenous 9-cis retinoic acid (9cRA) or all-trans retinoic acid (atRA) and analyzed histologically and immunohistochemically. Results: Retinoid receptors were expressed in a lineage-specific distribution, with stronger expression for many in the exocrine compartment. The receptors were not often expressed until late gestation. Exogenous 9cRA induced predominantly ducts instead of acini, plus more mature endocrine (islet) architecture. Exogenous atRA induced predominantly acini instead of ducts, with no apparent endocrine effect. Conclusions: Retinoids may have an important role in pancreatic differentiation, with a particular effect on secondary lineage selection between ductal and acinar phenotype. Because the control of ductal versus acinar differentiation has been implicated strongly in the pathogenesis of pancreatic ductal carcinoma, these results may lay the groundwork for studies in the mechanism of induced differentiation of pancreatic ductal cancer by retinoids. J Pediatr Surg 36:1150-1156. Copyright © 2001 by W.B. Saunders Company.

Cationic trypsinogen produced by human pancreatic ductal cancer has the characteristics of spontaneous activation and gelatinolytic activity in the presence of proton.

We examined whether human pancreatic ductal cancer cells express and secrete pancreatic cationic trypsinogen in vitro which can be spontaneously converted into active trypsin at acidic pH (pH 4.5-5. 5), in contrast to anionic trypsinogen. Cationic trypsinogen expression at the mRNA level was observed in differentiated Capan-1 and BxPC-3 cell lines. However, expression was not detected in either poorly-differentiated Panc-1 or undifferentiated MIAPaCa-2 cell line. The gelatinolytic activity of the activated form of trypsinogen in each conditioned medium in the presence of enterokinase (1.0 microg/ml) (a band with a molecular weight of approximately 23 kDa) corresponded well to the level of cationic trypsinogen mRNA. The spontaneous activation of trypsinogen also was observed by gelatin zymography of the acid-loaded conditioned medium (pH 5.5). These findings suggest that trypsinogen produced by human pancreatic ductal cancer has the characteristics of spontaneous activation and gelatinolytic activity in the presence of proton.

Establishment and characterization of a new, spontaneously immortalized, pancreatic ductal cell line from the Syrian golden hamster.

Spontaneously immortal pancreatic cell lines are not available. By use of a defined culture medium, such a line (TAKA-1) was established from the Syrian golden hamster. Cytological, cytogenetic, molecular biological, enzymatic and receptor patterns as well as antigenicity were studied and were compared with those of the normal hamster pancreatic ductal cells in vivo. TAKA-1 cells grew exponentially in a monolayer on collagen gel in a defined medium but did not proliferate in soft agar. Ultrastructurally, the cells closely resembled the normal hamster pancreatic ductal cells. Similarities and dissimilarities were found between the normal ductal cells and TAKA-1 cells. Similarities included the presence of cytokeratin, carbonic anhydrase and some tumor-associated antigens. However, unlike the normal ductal cells, TAKA-1 cells expressed blood group A antigen and anti-vimentin, showed affinity to selected lectins, and an abnormality of chromosome 3, which is suggested to be associated with immortality. Moreover, unlike the hamster pancreatic ductal cancer cells but like the normal hamster pancreatic ductal cells, TAKA-1 cells did not have a c-Ki-ras mutation. EGF, TGF-alpha and secretin, but not CCK or GRP, bound to the TAKA-1 cells. TAKA-1 cells produced TGF-alpha, and their growth was stimulated by exogenous EGF in serum-free medium. This cell line presents a suitable model for biologic and pathologic study of the hamster pancreatic ductal cells in vitro.

Cyclic-AMP-stimulated synthesis and release of carcinoembryonic antigen by pancreatic cancer cells.

The effect of cyclic adenosine 3':5'-monophosphate (cAMP) upon the synthesis and release of carcinoembryonic antigen (CEA) was studied in the human pancreatic ductal cancer cell line, SW-1990. Incubation for up to 24 h with forskolin, an activator of adenylate cyclase, or isobutylmethyl xanthine, a theophylline analog, increased cellular cAMP levels by over 100-fold and significantly increased CEA release and cellular CEA content. Whereas cAMP levels were augmented within 10 min of exposure to these agents, CEA release and CEA cell content were not increased until 90 min and 24 h, respectively. Similar results were obtained using dibutyryl-cAMP, a cAMP analog, but not using sodium butyrate, a metabolite of dibutyryl-cAMP. Cells were incubated with 35S-cysteine and 3H-glucosamine in the presence or absence of forskolin in order to compare the effects of high cAMP levels upon the synthesis and release of total proteins, total glycoproteins, and immunoprecipitable CEA. Both CEA synthesis and release were enhanced by forskolin, but these effects were not specific to CEA since the release of labeled proteins and glycoproteins also increased. In addition, altered CEA expression caused by forskolin was consistently associated with a cessation of cell division, an effect which was reversible upon removing the agent. There was no effect upon cell morphology or viability. The data indicate that increased levels of cellular cAMP in pancreatic cancer cells is associated with decreased cell proliferation and increased expression of CEA and other glycoproteins.