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...

Purpose: Hepatocellular carcinoma (HCC) associated with chronic liver disease is known to show an obvious multistage process of tumor progression. We previously identified heat shock protein 70 as a molecular marker of early HCC during investigation of expression profiling in multistage hepatocarcinogenesis. In this report, we examined cyclase-associated protein 2 (CAP2), which is also listed as an up-regulated gene in early HCC. Experimental Design: We measured the level of CAP2 mRNA by real-time quantitative PCR. We raised a polyclonal antibody against CAP2 and we confirmed the expression of CAP2 by immunoblotting and immunohistochemistry in HCC cell lines and HCC tissues. Results: According to real-time quantitative PCR, the level of CAP2 mRNA was up-regulated in early HCC when compared with noncancerous liver tissue, and it was further up-regulated in progressed HCC.We raised a polyclonal antibody against CAP2, which showed a single 53-kDa band of strong intensity in the human HCC cell lines and HCC tissues but only a weak band in the noncancerous liver tissues in Western blot analysis. Immunohistochemical examination of CAP2 revealed its significant overexpression in early HCC when compared with noncancerous and precancerous lesions and in progressed HCC when compared with early HCC. Conclusion: Our findings show that CAP2 is up-regulated in HCC when compared with noncancerous and precancerous lesions.This is the first report that proves that CAP2 is up-regulated in human cancers and that this is possibly related to multistage hepatocarcinogenesis.

A case of a primary carcinoid tumor within a polycystic kidney is reported. A 51-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) underwent a bilateral nephrectomy because of an infection in her polycystic kidneys. A tumor (1.5 cm in diameter) was incidentally found close to the hilum of the left kidney. Histologically, the tumor exhibited a predominantly trabecular pattern of cuboidal or columnar cells. Grimelius staining showed numerous silver-stained neurosecretory granules in most of the tumor cells; the tumor cells were also positive for chromogranin, synaptophysin, prostatic acid phosphatase (PAP) and neuron-specific enolase (NSE). The tumor was diagnosed as a primary carcinoid tumor of the kidney. Primary renal carcinoid is a very rare neoplasm, and this is the first report of such a lesion arising in a polycystic kidney.

Malignant bone tumors with epithelial differentiation are extremely rare. Only one case of primary malignant bone tumor with distinct squamous cell carcinoma and chondrosarcoma has ever been reported. Reported herein is a case of primary malignant bone tumor with distinct squamous cell carcinoma and chondrosarcoma, so-called carcinosarcoma of bone, arising in the femur of a 53-year-old man. The tumor was located within the femur and was diagnosed by curettage as a well-differentiated chondrosarcoma. No primary tumor was detected in any other organ. Within a few months the tumor had rapidly grown toward the soft tissue, and hemipelvectomy was performed. Examination of the surgical specimen revealed that the tumor was mainly composed of undifferentiated spindle sarcoma cells with scattered foci of chondrosarcoma and of squamous cell carcinoma with keratin pearl formation. The patient died approximately 6 months postoperatively. At autopsy multiple metastases were detected in the heart, both lungs, muscles, and lymph nodes. Interestingly, the chondrosarcoma and squamous cell carcinoma components were observed in several metastatic foci. The tumors in both the previously reported case and the present case contained components of chondrosarcoma and squamous cell carcinoma with keratin pearl formation, and this combination of histological features may be a unique characteristic of carcinosarcoma of bone.

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