Transferrin receptor is a marker of malignant phenotype in human pancreatic cancer and in neuroendocrine carcinoma of the pancreas

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Abstract

Transferrin receptor (TFRC) is a membrane-bound protein expressed in larger amounts in proliferating, e.g., malignant, cells than in quiescent cells. The specific expression of TFRC can represent a diagnostic tool or a therapeutic target in solid tumours expressing this antigen. Whether TFRC is expressed in human pancreatic tumours is unknown. The aim of this study was the investigation of the expression of TFRC and transferrin in human pancreatic cancer and in neuroendocrine tumours of the pancreas. Fifty one specimens of human pancreatic cancer and 14 samples of pancreatic neuroendocrine tumours were obtained after surgery. The expression of TFRC, transferrin and cytokeratin was studied by standard immunohistochemistry. Flow cytometry was used for the investigation of TFRC expression in nine cell lines of ductal pancreatic cancer in vitro. In contrast to normal tissue, 93% of pancreatic tumour cells showed positive (82%) or heterogeneous (11%) expression of TFRC. It was strongly expressed by malignant epithelial cells; normal stromal and endothelial cells were not stained by anti-TFRC antibodies. Primary tumours and metastases showed a similar frequency of TFRC expression. Three neuroendocrine carcinomas showed positive expression of TFRC by malignant tumour cells. The expression of TFRC was negative in benign neuroendocrine tumours of the pancreas. The cell lines of pancreatic cancer were characterised by a low expression of TFRC in vitro. In contrast to normal pancreatic tissue and benign neuroendocrine tumours of the pancreas, pancreatic cancer and neuroendocrine carcinoma are therefore characterised frequently by high expression of TFRC. Hence, TFRC represents a marker of malignant transformation in the pancreas that could be applied as potential diagnostic and therapeutic target.

Introduction

Ductal adenocarcinoma of the pancreas is still the fifth most common cause of cancer deaths in Europe and the USA [1]. The therapeutic results for pancreatic carcinoma are disappointing and the mean survival is very low. More than 80% of patients with pancreatic carcinoma come to clinical treatment in stage III or IV of tumour growth. Surgery is so far the only possibility for curing this malignant tumour. The mean survival time after diagnosis of pancreatic carcinoma does not exceed 6 months. Adjuvant therapeutic modalities such as chemo- and radiochemotherapy can increase the recurrence-free time, but do not improve the mean survival rates [1], [2], [3]. Despite attempted curative operations, only a minority of patients with ductal adenocarcinoma survive 5 years [4].

The development of specific molecular tracers for the diagnosis and treatment of this lethal cancer has a major goal. Advances in oncological research have led to the identification of many tumour-associated mutations. Some of them, such as p53, p16INK [5], ki-ras [6] and SMAD4 [1], [7] have been already evaluated as diagnostic factors in pancreatic carcinoma. However, the majority of these markers are characterised by limited specificity or sensitivity and can be used only in combination with conventional diagnostic tools [1].

Iron is an essential element for cell proliferation and cell metabolism. The high proliferative rates in malignant cells are characterised by an increased requirement for iron. For this purpose, cells have developed a specific mechanism for iron uptake from the plasma. The initial step in cellular iron uptake is the binding of transferrin–iron complexes to the transferrin receptor (TFRC) on the plasma membrane. After binding, this complex may be internalised. Because of its pivotal role in iron uptake, the TFRC is expressed in larger amounts in proliferating, e.g., malignant, cells than in quiescent cells [8]. Among normal tissues, the liver, epidermis, intestinal epithelium, brain endothelial cells as well as some populations of haematopoietic cells express constitutively the TFRC [8].

The TFRC is also expressed by most carcinomas, sarcomas and some lymphomas and leukaemias [9], [10], [11], [12]. Due to its increased expression by many malignant cells, the receptor has been suggested as a promising target in anti-cancer therapy [13].

Although the expression of TFRC was already well characterised in many malignant tumours, there have been no substantial reports about the role of this molecule in pancreatic tumours. A single investigation mentions two cases of pancreatic cancer that expressed TFRC [8]. In the present study, the expression of TFRC in human pancreatic carcinoma and in neuroendocrine tumours of the pancreas was investigated in a large number of tissue samples. This study demonstrated that TFRC is not expressed in normal pancreatic tissue and in most benign neuroendocrine tumours of the pancreas. TFRC was frequently upregulated in primary pancreatic cancer and its metastases, and in neuroendocrine carcinoma.

Section snippets

Patients and tissue samples

Patients admitted to the study were undergoing surgery for pancreatic tumours at the Department of Surgery of the University of Heidelberg. All gave their informed consent to the protocol, which was approved by the ethics committee at the University of Heidelberg. Fifty one samples of ductal pancreatic carcinoma (12 metastases and 39 primary tumours) and 12 samples of neuroendocrine tumours (five insulinomas, one gastrinoma, one glucagonoma, one carcinoid and four neuroendocrine carcinomas)

Transferrin receptor/transferrin

No samples of normal pancreatic tissue were stained by anti-TRFC antibodies. The expression of TFRC was also negative in most neuroendocrine tumours of the pancreas (all insulinomas, gastrinoma, glucagonoma and one neuroendocrine carcinoma) (Table 1). Three of the four neuroendocrine carcinomas were characterised by positive expression of TFRC that was strongly related to malignant tumour cells (Table 1; Fig. 1).

In contrast to normal tissue, 93% of pancreatic tumour cells showed positive (82%)

Discussion

The expression of TFRC in human pancreatic tumours had not, to the best of our knowledge, been analysed systematically before. There is only one report on the expression of transferrin receptor in normal pancreatic tissue and in two pancreatic cancer samples only [8]. We have investigated for the first time the expression of TFRC in a significant number of pancreatic cancers and in neuroendocrine tumours of the pancreas. We demonstrate that the TFRC was expressed exclusively by malignant cells

Acknowledgments

We thank C. Bernardi for her excellent assistance and D. Stefan for the help with the flow cytometric analysis.

References (19)

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