Purpose: Perineural invasion causes frequent local recurrence even after resection and a poor prognosis for pancreatic cancer. We established perineural invasion models and analyzed the molecular mechanism of perineural invasion in pancreatic cancer. Experimental Design: Seven pancreatic cancer cell lines with or without human peripheral nerves were s.c. implanted in nonobese diabetes/severe combined immunodeficient mice. We compared expression profiles among high and low perineural invasion cell lines by using an oligonucleotide microarray.We examined up-regulation of the invariant chain (CD74) in high perineural invasion cell lines in mRNA and protein levels and surgical cases immunohistochemically. Results: Four of seven pancreatic cancer cell lines (CaPan1, CaPan2, CFPAC, and MPanc96) showed perineural invasion to s.c. transplanted human peripheral nerves. Moreover, CaPan1and CaPan2 (high perineural invasion group) also resulted in a high frequency of perineural invasion to mouse s.c. peripheral nerves, whereas three pancreatic cancer cell lines HPAFII, AsPC1, and Panc1 (low perineural invasion group) did not show perineural invasion to either human or mouse nerves. We identified 37 up-regulated genes and 12 down-regulated genes in the high perineural invasion group compared with the low perineural invasion group. Among them, CD74 was up-regulated in the high perineural invasion group in mRNA and protein levels. Furthermore, immunohistochemical expression of CD74 in clinical cases revealed its significant overexpression in pancreatic cancer with perineural invasion (P < 0.008).Conclusions:This is the first report of perineural invasion models using human pancreatic cancer cell lines. In combination with gene expression profiling, it was indicated that CD74 could be a candidate molecule involved in perineural invasion. These models provide new approaches for study of perineural invasion in pancreatic cancer.Pancreatic cancer is the fourth leading cause of cancer-related death in the United States (1). Worldwide pancreatic cancer causes an estimated 213,000 deaths a year (2). In the United States, f32,180 patients are diagnosed with pancreatic cancer annually, and nearly an equal number will die from the disease (1). When first diagnosed with pancreatic cancer, about 80% of all patients receive palliative therapy instead of surgery because of locally advanced disease, depending on perineural invasion or metastasis. The remaining 20% of patients receiving surgery still have a poor prognosis due to high incidence and early occurrence of local recurrence and hepatic and lymph node metastasis, even after pathologically curative surgery (3 -5). It is suspected that microscopic hepatic metastasis is already present (6). Cancer cells spreading in the perineural space even at an early clinical stage also cause local recurrence in the retroperitoneum because of residual tumor cells in the perineural space after surgical resection (7). Moreover, many previous clinicopathologic reports showed that perineural i...