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 two-fold 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.

中文翻译：

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拓扑结构影响 TRAIL 治疗：胰腺导管腺癌细胞原位和皮下异种移植之间原发癌生长和肝转移的差异

 背景

为了研究胰腺导管腺癌（PDAC）的新治疗方式，我们需要将知识从体外转移到体内。重要的是要反映胰腺癌典型的局部侵袭性生长和导致肝转移的远处扩散的临床特征。值得注意的是，对于使用人类标本的异种移植研究，广泛使用两种模型，即皮下（sc）和原位（ot）移植。

 方法

直接比较皮下和原位接种的 Colo357 Bcl-x _L细胞衍生肿瘤是否接受 TNF 相关凋亡诱导配体 (TRAIL) 治疗。评估原发肿瘤的大小、肝转移的数量以及组织学标志物Ki67、M30、TNF-α和CD31。

 结果

TRAIL 治疗后，无论是皮下还是 ot 方法，原发肿瘤的大小都没有改变。但当 sc 与 ot 比较时，sc 肿瘤的大小是 ot 肿瘤的两倍多（ P < 0.01）。然而，原位接种 PDAC 细胞的小鼠在 TRAIL 治疗后发生肝转移的频率 ( n = 13/17) 比皮下接种 PDAC 细胞的小鼠 ( n = 1/11) 更频繁 ( P < 0.01)。作为这种转移增加的可能驱动力，通过免疫组织化学观察到肿瘤中较高的 TNF-α 染色强度。

 结论

这些来自直接并排比较的数据强调了 PDAC 细胞正确接种位点的重要性。局部侵袭和肝转移是PDAC在临床上的一个标志； ot 模型在反映这种设置方面显然更胜一筹。此外，一种可能的新治疗化合物的严重副作用仅在 ot 模型中才变得明显。