Topology impacts TRAIL therapy: Differences in primary cancer growth and liver metastasis between orthotopic and subcutaneous xenotransplants of pancreatic ductal adenocarcinoma cells

Background: To study novel treatment modalities for pancreatic ductal adenocarcinoma(PDAC), we need to transfer the knowledge from in vitro to in vivo. It is important to mirror the clinical characteristics of the typically local invasive growth of pancreatic cancer and the distant spread resulting in liver metastasis. Notably, for xenotransplant studies using human specimen, two models, i.e. subcutaneous(s.c.) and orthotopic(o.t.) transplantation are widely used. Methods: The subcutaneously and orthotopically inoculated Colo357 Bcl-x L cell-derived tumors were directly compared with and without TNF-related apoptosis inducing ligand(TRAIL) treatment. The size of primary tumors, number of liver metastasis and the histologic markers Ki67, M30, TNF-α and CD31 were assessed. Results: Upon TRAIL treatment, the primary tumors did not change their size, neither in the s.c. nor in the o.t. approaches. But when s.c. was compared to o.t., the size of the s.c. tumors was more than twofold bigger than that of the o.t. tumors( P<0.01). However, mice with orthotopically inoculated PDAC cells developed liver metastasis upon TRAIL treatment much more frequently( n=13/17) than mice with subcutaneously inoculated PDAC cells( n=1/11)( P<0.01). As a likely driving force for this increased metastasis, a higher TNF-α staining intensity in the o.t. tumors was observed by immunohistochemistry. Conclusions: These data from a direct side-by-side comparison underline the importance of the proper inoculation site of the PDAC cells. Local invasion and liver metastases are a hallmark of PDAC in the clinic;the o.t. model is clearly superior in reflecting this setting. Moreover, a serious side-effect of a possible new therapeutic compound became obvious only in the o.t. model.

Subcutaneous and breast metastasis from asymptomatic gallbladder carcinoma

BACKGROUND:Though gallbladder carcinoma is asso- ciated with early lymphatic and hematogenous spread, the only common extra-abdominal site of metastasis is lung.Gallbladder carcinoma metastasizing to breast and subcutaneous tissue is not known. METHOD:This report describes an interesting and unusual case of asymptomatic gallbladder carcinoma presenting with subcutaneous and breast metastasis. RESULTS:A 42-year-old woman presented with multiple subcutaneous nodules over the abdominal wall,anterior chest wall,back and in bilateral breasts.Fine needle aspiration cytology(FNAC)of these nodules revealed metastatic adenocarcinoma.The patient was investigated for a primary neoplasm.An ultrasound of the abdomen followed by a contrast-enhanced CT scan showed a growth in gallbladder,infiltrating the liver with multiple hepatic metastases.CT-guided FNAC from the growth in the gallbladder revealed adenocarcinoma.She was diagnosed as a case of metastatic adenocarcinoma of the gallbladder and palliative combination chemotherapy with gemcitabine and carboplatin was given.But she developed jaundice and deteriorated dramatically in a short span of time.No specific therapy could be started and she was given supportive treatment.She died within three weeks of diagnosis due to hepatic encephalopathy. CONCLUSIONS:This report highlights an unusual metastasis of gallbladder carcinoma to the breast and subcutaneous tissue presenting as multiple lesions,which has never been reported in the English literature.These were unknown sites of metastasis for carcinoma of the gallbladder.Moreover,bilateral multiple metastatic lesions to breast are also very rare.