Differentiation and DNA Synthesis in Pancreatic Acinar Carcinoma of Rat

Morphological analysis of transplantable pancreatic acinar carcinoma of rat has revealed a continuum of cells from those which totally lack mature secretory granules to cells with abundant well-formed secretory granules. This tumor is easily dissociable into single cells which incorporate [³H]thymidine and [³H]leucine into DNA and protein at a linear rate for 3 to 4 hr. The number of cells synthesizing DNA, as assessed by light microscope autoradiography, was about 17%. Dissociated neoplastic pancreatic acinar cells are classified into four cell types (types I to IV) on the basis of nuclear morphology, degree of polarization, and the extent of specialization of cytoplasmic organelles. Type IV cells possess all the characteristics of mature pancreatic acinar cells, such as abundant rough endoplasmic reticulum, prominent Golgi apparatus, and numerous secretory granules. Cell types III, II, and I are progressively less differentiated. An analysis of the cytological features of 285 dissociated tumor cells revealed the following distribution: type I cells, 21% type II cells, 23% type III cells, 22% and type IV cells, 34%. Analysis of the cytological features of 233 [³H]thymidine-labeled cells in high-resolution autoradiograms indicated that all four types of neoplastic pancreatic acinar cells are capable of DNA synthesis and revealed the following distribution: type I, 14% type II, 28% type III, 21% and type IV, 37%. The observation that all four types of neoplastic acinar cells are capable of DNA synthesis indicates that cell proliferation and differentiation in this neoplasm are not mutually exclusive. An analysis of 135 mitotic cells for the presence or absence of secretory granules revealed the presence of secretory granules in about 65% of mitotic tumor cells. This observation indicates that neoplastic pancreatic acinar cells with differentiated phenotype continue to divide even in a fully mature state. Disproportionate partitioning of secretory granules observed in some cells during mitosis suggests that such a process could yield both mature (type IV) and immature (type III or lower) daughter cells. These studies demonstrate that the mature neoplastic pancreatic acinar cell is capable of synthesizing DNA and that it can apparently acquire immature phenotypic characteristics (i.e., retrodifferentiate) as a result of continued mitosis without adequate interphase time for cytodifferentiation.