Int J Colorectal Dis (2002) 17:42–45 DOI 10.1007/s003840100345
Daniel C. Damin Mário A. Rosito Pedro Gus Israel Roisemberg Eliane Bandinelli Gilberto Schwartsmann
Accepted: 11 July 2001 Published online: 18 August 2001 © Springer-Verlag 2001
D.C. Damin (✉) · M.A. Rosito · P. Gus Department of Coloproctological Surgery, Federal University of Rio Grande do Sul, Porto Alegre, Brazil e-mail:
[email protected] Tel.: +55-51-3416816 Fax: +55-51-3286810 I. Roisemberg · E. Bandinelli Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Brazil G. Schwartsmann Postgraduate Course in Medicine, Federal University of Rio Grande do Sul, Comprehensive Cancer Center, The Lutheran University, Porto Alegre, Brazil D.C. Damin Rua Carlos Legori 220, suit 201, Porto Alegre RS, 91340-150 Brazil
O R I G I N A L A RT I C L E
Von Willebrand factor in colorectal cancer
Abstract Background and aim: Von Willebrand factor (vWF) is a protein that mediates adherence of platelets to subendothelium during primary hemostasis. High vWF plasma concentrations have been reported in patients with various types of cancer, such as squamous cell carcinoma of the larynx and the cervix. This effect is associated with tumor-related angiogenesis and the metastatic process. The aim of this study was to determine plasma levels of vWF in a series of patients with colorectal carcinoma and the correlation of these values with specific prognostic predictors for the disease. Patients and methods: vWF was measured by quantitative immunoelectrophoresis in 75 patients with colorectal carcinoma at various Dukes’ stages and compared with results from 88 healthy controls. Results: Cancer patients had significantly higher vWF concentrations than controls. vWF plasma levels were associated with tumor staging, invasion of adjacent or-
Introduction Although many prognostic factors for colorectal cancer have been studied, tumor staging remains the most important predictor of disease outcome. Patients classified as having Dukes’ stage D have the poorest prognosis, with 5-year survival rates of approx. 5% [1, 2, 3]. Distant metastases are found in 75% of individuals dying from the disease [4].
gans by the tumor, and presence of distant metastases. There was no significant correlation between vWF values and tumor size, histological grading, or plasma carcinoembryonic antigen levels. Conclusions: The levels of vWF are elevated in patients with colorectal cancer, and these values tend to increase with tumor progression. Considering that vWF is related to the process of tumor angiogenesis and may contribute to metastatic dissemination of malignant cells, further studies of its potential role as a marker of tumor progression in patients with colorectal cancer are warranted. It should be pointed out, however, that these observations need to be substantiated with additional studies using other methods and, preferably, the determination of vWF levels synthesized in the tumor tissues. Keywords Von Willebrand factor · Colorectal carcinoma · Colon cancer
The development of metastases is a stepwise process that starts with the establishment and expansion of tumor cell clones with angiogenic properties. The angiogenic process depends upon the capacity of tumor cells to interact with the stroma and produce growth factors that stimulate the proliferation of endothelial cells in the tumor bed. This results in the formation of new blood vessels which allow the exponential growth of tumor cells and their passage to the circulation [5, 6, 7]. There is
43
strong evidence this neovascularization is associated with the increase in von Willebrand factor (vWF) levels in plasma [8, 9]. vWF is a glycoprotein synthesized mainly in endothelial cells and in megakaryocites [10, 11]. It plays an essential role in primary hemostasis, mediating adhesion of platelets to subendothelial surfaces at sites of vascular injury and acting as a carrier protein for coagulation factor VIII [12]. Increased plasma concentrations of vWF have been reported in several clinical conditions such as liver diseases, diabetes mellitus, myocardial infarction, connective tissue diseases, and acute infections, probably as result of increased endothelial cells proliferation or as part of the acute-phase reaction in response to vascular damage [13, 14, 15, 16, 17]. Plasma levels are also affected by AB0 blood group, with individuals of group 0 having the lowest mean vWF concentrations [18]. Experimental models have shown vWF to be very important in pathogenesis of metastasis, by promoting the binding of tumor cells to platelets. This interaction forms heterotypic cellular emboli, which are not recognized by the immune system and have more chance of attachment to the endothelial surfaces than single tumor cells [19, 20, 21, 22]. Recent clinical studies suggest that levels of vWF in plasma of patients with various types of cancer increase with tumor staging and may have prognostic significance [23, 24, 25, 26, 27]. The present study measured levels of vWF in plasma of a large series of patients with colorectal carcinoma to investigate its correlation with malignant phenotype and known prognostic factors in the disease.
Table 2 Location of cancers in the bowel
Site
n
%
Rectum Left colon Right colon Transverse colon Multiple sites
39 21 10 3 2
52.0 28.0 13.3 4.0 2.7
The study was performed after agreement of the Ethics and Scientific Committee of the Hospital de Clínicas de Porto Alegre. Informed consent was obtained from patients and controls before study entry. Prestudy evaluation Patients had to undergo a routine staging procedure which included a complete medical history and physical examination, full blood counts, biochemistry, liver and renal tests, carcinoembryonic antigen measurement, and imaging tests (chest radiography, abdominal ultrasound, or computed tomography and other tests when indicated). A complete coagulation assessment was performed in all patients and included a total platelet count, prothrombin time, partial thromboplastin time, and the measurements of coagulation factors. Laboratory measurements vWF was measured through its plasma antigen. Blood samples were drawn by venipuncture before operation and collected into 1:10 volume 3.8% trisodium citrate. After centrifugation at 3500 g for 15 min the platelet-poor plasma was stored at –80°C until used. The vWF levels were measured by quantitative immunoelectrophoresis technique, using a rabbit polyclonal antibody against human vWF [29]. The plasma levels of vWF antigen were expressed in units per deciliter.
Materials and methods Statistical analysis
Patients This study consisted of 75 newly diagnosed patients with histologically confirmed colorectal carcinoma and 88 healthy controls, randomly selected from a pool of blood donors. The main characteristics of the patients and controls are summarized in Table 1. The distribution of tumors in the various segments of the large bowel is shown in Table 2. None of the patients or controls suffered from any associated clinical condition capable of altering vWF plasma levels, such as diabetes mellitus, connective tissue disorders, or coronary artery disease. Other inclusion criteria included no prior surgery, radiation, or cytotoxic therapy for the colorectal cancer. The patients were categorized into stages according to the Dukes classification as modified by Turnbull et al. [28]. Table 1 Characteristics of the cancer patients and healthy controls
Sex: M/F Mean age (years) Blood type 0 White race
Patients (n=75)
Controls (n=87)
P
37 (49.3%) 60.2±14.8 32 (42.7%) 73 (97.3)
44 (50.6%) 50±6.1 37 (42.5%) 86 (98.9)
0.87 0.001 0.99 0.86
The results obtained in patients and controls were compared by Student’s t test. Differences in mean ages between patients and controls were adjusted by multiple regression analysis. Evaluation of quantitative data among three or more groups was made through one-way analysis of variance. Categorical data were tested by the χ2 test for contingence tables.
Results The mean plasma level of vWF was 230.6±96 U/dl in patients with cancer and 150.2±58 U/dl in controls (P
