ORIGINAL CONTRIBUTION
Preoperative Serum Placenta Growth Factor Level Is a Prognostic Biomarker in Colorectal Cancer Shu-Chen Wei, M.D., Ph.D.1 • Jin-Tung Liang, M.D., Ph.D.2 Po-Nien Tsao, M.D., Ph.D.3 • Fon-Jou Hsieh, M.D.4 • Sen-Chang Yu, M.D.5 Jau-Min Wong, M.D., Ph.D.1 1 Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan 2 Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan 3 Department of Pediatrics, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan 4 Department of Obstetrics and Gynecology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan 5 Department of General Surgery, Taipei Branch of the Buddhist Tzu Chi General Hospital, Taipei, Taiwan
PURPOSE: Increased angiogenesis at the site of the primary tumor in colorectal cancer has been associated with poor prognosis and relapse of disease. We previously demonstrated that the tissue level of placenta growth factor expression was upregulated in colorectal cancer and correlated with disease progression and patient survival. The aims of this study are to examine the prognostic value of serum placenta growth factor, vascular endothelial growth factor, and sFlt-1 and to compare them with the carcinoembryonic antigen levels in patients with colorectal cancer.
preoperative serum placenta growth factor as a cutoff point, the sensitivity, specificity, and positive predictive value for tumor recurrence and survival was 80, 54, 80% and 70, 56, 70%, respectively.
METHODS: Preoperative serum from 86 patients and
KEY WORDS: Serum; Placenta growth factor; Vascular endothelial growth factor; sFlt-1; Carcinoembryonic antigen; Colorectal cancer.
serum from 30 healthy controls was included. The levels of sFlt-1, placenta growth factor, vascular endothelial growth factor in the serum were assayed and correlated with the clinical stage results. RESULTS: Serum placenta growth factor, but not vascular endothelial growth factor, increased; sFlt-1 decreased in patients with preoperative colorectal cancer, compared with healthy controls. Higher preoperation serum placenta growth factor levels were associated with higher risk of recurrence. Preoperation serum placenta growth factor, but not carcinoembryonic antigen, was a prognostic indicator in patients with Stage III colorectal cancer. When we use the median level (20.6 pg/ml) of
Supported by the National Science Council of Taiwan Grant NSC-0952314-B-002-138. Address of correspondence: Shu-Chen Wei, M.D., Ph.D., Department of Internal Medicine, National Taiwan University Hospital, No. 7 Chung Shan South Road, Taipei, Taiwan. E-mail:
[email protected] Dis Colon Rectum 2009; 52: 1630 –1636 DOI: 10.1007/DCR.0b013e3181afbdaf ©The ASCRS 2009
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CONCLUSIONS: Preoperative serum placenta growth
factor levels were higher in patients with colorectal cancer, were negatively correlated with the serum sFlt-1, and could be used as a prognostic indicator for recurrence and survival for colorectal cancer.
olorectal cancer (CRC), one of the most common cancers worldwide, is the second leading cause of death from cancer in Western countries1 and the third most common cancer in Taiwan.2 Prognosis of these patients mainly depends on the tumor stage at diagnosis. The fact that tumor growth and metastasis rely on angiogenesis has been widely accepted.3 Increased angiogenesis in the primary tumor of colorectal cancer has been associated with poor prognosis and relapse of disease.4,5 Many angiogenic factors have been identified that regulate angiogenesis in colon cancer. Vascular endothelial growth factor (VEGF) has been shown to be upregulated in the progression from nonmetastatic to metastatic colon cancers.6 –11 Furthermore, high levels of VEGF expression and elevated vessel counts were found to correlate with recurrence and metastasis of colon cancer, suggesting that VEGF expression could serve as an indicator of colorectal cancer prognosis. However, most studies showed that VEGF expression at the tissue level is not a good predictor of prognosis.8,12,13 Placenta growth factor (PlGF), a dimeric glycoprotein
C
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with 53% homology to VEGF,14,15 which binds to VEGF receptor-1 (Flt-1), but not to VEGF receptor-2 (Flk-1), may function by modulating VEGF activity.16 Flt-1 exists in two forms due to alternative splicing: the full-length receptor, which transmits angiogenic signals, and a soluble secreted form of Flt-1 (sFlt-1), which lacks the transmenbrane and cytoplasmic domains but retains the ability to bind to its ligands. These characteristics contribute to the function of sFlt-1 as a dominant-negative inhibitor of VEGF and PlGF.17 Recently, several reports showed that in gastric cancer, breast cancer, renal cell cancer, and nonsmall cell lung cancer in humans, PlGF was overexpressed and displayed prognostic value.18 –21 In our previous report, we demonstrated that the PlGF mRNA expression was upregulated in colorectal cancer tissue. The extent of upregulation correlated with disease progression and patient survival. Therefore, our results suggest that expression levels of PlGF in CRC may be used as a prognostic marker for patients with colorectal cancer.2 Because serologic biomarkers can be analyzed noninvasively and can be applied more practically and economically, they have the potential to be developed as prognostic indicators for colorectal cancer. Previously, Matsumoto et al.21 showed that plasma PlGF levels were associated with the clinical features of renal cell carcinoma, with prognostic significance. However, the predictive value of serum PlGF levels in patients with CRC remains unknown. The aim of this study is to examine the prognostic value of serum PlGF, VEGF, and sFlt-1 and to compare them with carcinoembryonic antigen (CEA) levels in patients with colorectal cancer.
provided by Dr. Chun-Jen Yen (Department of Internal Medicine, National Taiwan University Hospital). Measurements
The levels of sFlt-1, PlGF, and VEGF in serum and the expression levels of PlGF in the colorectal cancer were assayed by a standardized sandwich enzyme-linked immunosorbent assay (ELISA; R&D Systems, Minneapolis, MN) in triplicate according to the protocol recommended by the manufacturer. Enzyme-Linked Immunosorbent Assay
Serum samples were kept at ⫺80°C until use. Concentrations of serum PlGF were quantified with use of a Quantikine® human PlGF immunoassay (R&D Systems, Inc., Minneapolis, MN). Sera were incubated overnight at 4°C on microtiter plates coated with a murine monoclonal antibody against human PlGF. Unbound proteins were washed off, and an enzyme-linked polyclonal antibody specific for PlGF is added to “sandwich” the PlGF immobilized during the first incubation. A substrate solution for horseradish peroxidase was added, and color was developed in proportion to the amount of antibody-bound PlGF. The absorbance of the color was read at 450 nm. A standard curve, consisting of known amounts of PlGF, was carried through the above procedure, and the concentrations of PlGF in the unknown samples were determined from this standard curve. Concentrations of PlGF were expressed as picograms per milligram protein. Similar methods were applied for measuring the serum VEGF and sFlt-1 (ELISA kit, R&D Systems, Minneapolis, MN). Data Analysis
MATERIALS AND METHODS Materials
The serum and clinical data from a total of 86 patients were included. These samples were collected from September 2000 to March 2002, following the guidelines set forth by the Ethical Committee of the National Taiwan University Hospital. All sera were collected before surgery. Clinical staging of cancers was determined based on the International Union against Cancer TNM classification. All patients received the identical treatment program in this study. No presurgical chemotherapy or radiotherapy was given for the colon cancer group, whereas patients with Stage III and IV colon cancer were subjected to postoperative chemotherapy with 5-fluorouracil and leucovorin. Follow-up duration was defined as the period between the operation date and the date of the last visit according to the patient’s chart. Recurrence was defined as the discovery of either metachronous CRC or distal metastasis. CEA levels were pursued from the chart record, which was checked before the surgery, and analyzed. Serum from 30 agematched and gender-matched healthy controls was kindly
Statistical analysis was performed by SPSS® 12.0 software (Chicago, IL). Correlations between serum PlGF, VEGF, sFlt-1, and CEA levels and clinical stages, were analyzed by Spearman’s correlation coefficient. The Mann-Whitney U test was used for comparing the control and patient data. A survival curve was obtained with use of the Kaplan-Meier method. Differences in cancer-specific survival time for patients with tumors of high or low expression levels (median as cutoff point) of PlGF, VEGF, sFlt-1, or CEA were analyzed with the log-rank test. Cox proportional hazards regression model was used for multivariant analysis. P ⬍ 0.05 was defined as statistical significance.
RESULTS Patient Baseline Characteristics
A total of 86 consecutive patients with histologically confirmed CRC were recruited. Baseline characteristics are listed in Table 1. There were 29 rectal cancers and 57 colon cancers. The stage breakdown of the patients was Stage I, 9; Stage II, 30; Stage III, 32; Stage IV, 15. The mean age at
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TABLE 1. Patients baseline characteristics Characteristics CRC patients Age (years) Median Range Sex Male Female Tumor stage I II III IV Tumor localization Colon Rectum Recurrence Survival CEA Median Range VEGF levels (pg/ml) Median Range PlGF levels (pg/ml) Median Range sFlt-1 levels (pg/ml) Median Range
No. of patients
Values
86 67 26–88
CRC patients (median, 79.7 pg/ml; range, 0 –1159 pg/ml) and healthy controls (median, 60.9 pg/ml; range, 18.3–136.54 pg/ml) (Fig. 1B), although the median level was higher in CRC patients than in the normal controls. The preoperative serum sFlt-1 level was significantly lower in the CRC patients (median, 75.4 pg/ml; range, 0 –2291.3
52 34 9 30 32 15 57 29 10 66 2.4 0.4–73 79.7 0–1159 20.6 0–60.4 75.4 2–2291.3
CRC ⫽ colorectal cancer; CEA ⫽ carcinoembryonic antigen; PlGF ⫽ placenta growth factor; VEGF, vascular endothelial growth factor; sFlt-1 ⫽ soluble secreted form of Flt-1.
diagnosis of CRC was 64.0 years; there were 52 male patients and 34 female patients. The follow-up period ranged from 6 to 56 months (median, 36). Ten patients had recurrence and 20 patients died of CRC during the follow-up period. Among the patients with disease recurrence, four had metachronous tumors (previously staged as Stage II in three patients and Stage III in one patient), the other six patients had liver metastasis (previously staged as Stage III in five patients and Stage II in one patient). Serum PlGF, but not VEGF, Increased; sFlt-1 Decreased in Preoperative CRC Patients Compared with Healthy Controls
Preoperative PlGF levels were significantly increased in patients with colorectal cancer (median, 20.6 pg/ml; range, 0 – 60.4 pg/ml), compared with the levels in healthy controls (median, 12.0 pg/ml; range, 4.7–17.7 pg/ml) (P ⫽ 0.02) (Fig. 1A). The serum PlGF levels were not significantly associated with a TNM stage of disease (P ⫽ 0.48), gender (P ⫽ 0.74), age (P ⫽ 0.80), or tumor location, (rectum or colon) (P ⫽ 0.23). In contrast to PlGF levels, the serum VEGF levels showed no significant difference (P ⫽ 0.48) between the
FIGURE 1. The preoperative CRC patient serum levels of PlGF (A), VEGF (B), and sFlt-1 (C), compared with healthy controls. CRC ⫽ colorectal cancer; PlGF ⫽ placenta growth factor; VEGF, vascular endothelial growth factor; sFlt-1 ⫽ soluble secreted form of Flt-1.
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pg/ml), compared with healthy controls (median, 187.3 pg/ml; range, 59.8 –273.4 pg/ml) (P ⬍ 0.001) (Fig. 1C). With Spearman’s correlation analysis, serum sFlt-1 was significantly negatively correlated with serum PlGF (r ⫽ ⫺0.375, P ⬍ 0.001). The same method has been used for checking the correlation between each one of the serum markers (PlGF, VEGF, or sFlt-1) and CEA, and results showed no significant correlation between all the markers and CEA (r ⫽ 0.13, 0.21, 0.08 and P ⫽ 0.25, 0.09, 0.53, respectively). A Higher Preoperative Serum PlGF Level Is Associated with Higher Risk of Recurrence
Statistical analysis of time to any recurrence showed a significant association between the preoperative PlGF levels and recurrent disease (Fig. 2), with high PlGF levels associated with increased risk of recurrent disease (P ⫽ 0.029, log-rank test). In addition, high serum CEA levels (P ⫽ 0.002) and tumor of the rectum (P ⫽ 0.01) also correlated with increased risk of recurrent disease. Applying multivariate analysis with the inclusion of age, gender, TNM stage of disease, tumor location, serum PlGF, VEGF, sFlt-1, and CEA levels in the curatively treated patients (TNM Stage I to Stage III, n ⫽ 71) showed that only the preoperative PlGF level (P ⫽ 0.008) had prognostic value with respect to recurrence (Table 2). When we used the median value of preoperative serum PlGF (20.6 pg/ml) as a cutoff point, the sensitivity, specificity, and positive predictive value for tumor recurrence was 80, 54, and 80%, respectively. Serum PlGF Level Is a Prognostic Factor in Patients with CRC
Patients were arbitrarily assigned to the lower or higher serum PlGF group, based on whether they had lower or
TABLE 2. Multivariate analysis estimating recurrent CRC disease in patients considered curatively operated Covariate Age (years) Sex (female/male) Stage Tumor location (colon/rectum) CEA levels (⬎3 to ⬍3 ng/ml) Serum PlGF levels (higher than median to lower than median) Serum VEGF levels (higher than median to lower than median) Serum sFlt-1 levels (higher than median to lower than median)
P value
HR (95% CI)
0.962 0.174 0.739 0.428 0.661 0.008
1.00 (0.98–1.03)a 1.59 (0.81–3.12) 1.06 (0.74–1.53)a 1.37 (0.63–3.00) 0.86 (0.43–1.71) 2.46 (1.27–4.78)
0.240
1.49 (0.77–2.90)
0.217
0.67 (0.35–1.27)
HR ⫽ hazard ratio; CI ⫽ confidence interval; CEA ⫽ carcinoembryonic antigen; PlGF ⫽ placenta growth factor; VEGF, vascular endothelial growth factor; sFlt-1 ⫽ soluble secreted form of Flt-1. a The HR estimated for age is per one-year increase and the HR for stage is per onestage increase.
higher PlGF levels than the median value. The probability of cancer-specific survival was significantly lower in the higher serum PlGF level group than the lower serum PlGF level group (log-rank test, P ⫽ 0.014; median follow-up, 36 months) (Fig. 3A). When using the median value (20.6 pg/ml) of preoperative serum PlGF as the cutoff point, the sensitivity, specificity, and positive predictive value for survival is 70, 56, and 70%, respectively. In contrast, there was no statistical difference between the probabilities of cancer-specific survival in the higher and lower serum VEGF level (P ⫽ 0.38) and serum sFlt-1 level (P ⫽ 0.77). In addition to serum PlGF level, the probability of cancer-specific survival was also significantly lower in the higher serum CEA level group (P ⫽ 0.008) (Fig. 3B). When analyzed with the extended Cox regression model, higher serum PlGF level, stage, and CEA were shown to have a statistically independent prognostic value with respect to survival (Table 3), compared with the other factors (age, gender, tumor location, serum VEGF, and sFlt-1 levels). Preoperative serum PlGF, but not CEA, was a prognostic indicator in Stage III CRC patients. Currently, there is no good prognostic indicator for Stage II and Stage III CRC patients. Because CEA and serum PlGF have independent prognostic values as shown above, we tested further whether they have prognostic value in Stage II and Stage III CRC patients. In Stage II patients, both higher serum PlGF (P ⫽ 0.08) and higher CEA (P ⫽ 0.054) levels showed only a trend that associated with poor prognosis in patients. However, in Stage III patients, a higher serum PlGF level was associated with poor survival (P ⫽ 0.02; Fig. 3C), but not high CEA level (P ⫽ 0.07).
DISCUSSION FIGURE 2. Higher preoperative serum PlGF level associated with higher CRC recurrence. PlGF ⫽ placenta growth factor; CRC ⫽ colorectal cancer.
We reported previously that PlGF expression levels in tissue are an indicator of CRC patient survival.2 In this re-
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port, with use of recurrence and survival as the outcome indicators, we further demonstrate that preoperative serum PlGF levels in CRC patients is an independent, powerful predictor of their prognosis. There was no association between the serum levels of PlGF and the tumor stages or tumor location, but patients with higher serum PlGF levels tended to have a significantly poorer prognosis, compared with patients with lower serum PlGF levels. Moreover, especially in the Stage III CRC patients, serum PlGF, but not CEA, was found to be an indicator for survival. However, because the case numbers for recurrence and survival are both small, there might be a possibility of model overfitting for statistical analysis. Further large-series studies could help us to confirm the results. Flt-1 exists in two forms as a result of alternative splicing: the full-length receptor, which transmits angiogenic signals, and a soluble secreted form of Flt-1 (sFlt-1), which lacks the transmembrane and cytoplasmic domains but retains the ability to bind to its ligands. These characteristics make sFlt-1 function as a dominant-negative inhibitor against VEGF and PlGF.17,22 Serum sFlt-1 has been reported to be an antiangiogenesis factor that can inhibit tumor growth and metastasis.23 According to our results, the preoperative serum sFlt-1 was decreased in the serum of CRC patients, compared with the levels of the control group. Caine et al 24 reported similar findings in patients with breast cancer. These results suggest that sFlt-1, which functions in the angiogenesis and carcinogenesis in colorectal cancer, might be used as a serum marker for cancer screen. At the tissue level, elevated expression of VEGF in patients with colorectal cancer was observed in many studies.6 –12 In general, there was no correlation between elevated VEGF expression and patient survival, with only one exception, that of Lee et al. who reported that VEGF correlated with survival. However, it did not emerge as an
TABLE 3. Multivariate analysis for survival in patients with CRC disease Covariate
FIGURE 3. Preoperative serum PlGF (A) and CEA (B) levels are prognostic factors of CRC patient survival status. PlGF is a particular prognostic factor for survival of Stage III CRC patients (C). PlGF ⫽ placenta growth factor; CEA ⫽ carcinoembryonic antigen; CRC ⫽ colorectal cancer.
Age (years) Sex (F/M) Stage Tumor location (colon/rectum) CEA levels (⬎3 to ⬍3 ng/ml) Serum PlGF levels (higher than median to lower than median) Serum VEGF levels (higher than median to lower than median) Serum sFlt-1 levels (higher than median to lower than median)
P value
HR (95% CI)
0.876 0.452 0.002 0.072 0.007 0.048
1.00 (0.96–1.04)a 1.63 (0.46–5.80) 3.2 (1.52–6.73)a 0.32 (0.09–1.11) 5.43 (1.61–18.38) 3.20 (1.01–10.1)
0.792
0.85 (0.27–2.75)
0.535
1.47 (0.44–4.95)
HR ⫽ hazard ratio; CI ⫽ confidence interval; CEA ⫽ carcinoembryonic antigen; PlGF ⫽ placenta growth factor; VEGF, vascular endothelial growth factor; sFlt-1 ⫽ soluble secreted form of Flt-1. a The HR estimated for age is per one-year increase and the HR for stage is per onestage increase
DISEASES OF THE COLON & RECTUM VOLUME 52: 9 (2009)
independent risk factor in a multivariate analysis.6 At about the serum level of VEGF in CRC patients, it has been reported that serum VEGF is elevated in CRC patients,25–28 and correlated with the tumor stages and outcomes (metastasis and survival). However, more recently, it has been reported that there is no difference of serum VEGF between CRC patients and the control group, and preoperative VEGF is not a marker for subsequent recurrence.29,30 Our results also showed that there were no differences in preoperative serum VEGF levels between CRC patients and the controls. In addition, there was no correlation between outcome and serum VEGF. The difference might come from the sampling (patient number in each tumor stage). In summary, we demonstrate here that preoperative serum PlGF was higher in CRC patients and it was negatively correlated with the serum sFlt-1. Preoperative serum PlGF could be used as a prognostic indicator for recurrence and survival of CRC. ACKNOWLEDGMENT The authors thank the second Core Laboratory of the Department of Medical Research of the National Taiwan University Hospital for technical assistance. REFERENCES 1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8 –29. 2. Wei SC, Tsao PN, Yu SC, et al. Placenta growth factor expression is correlated with survival of patients with colorectal cancer. Gut 2005;54:666 –72. 3. Stoeltzing O, Liu W, Reinmuth N, et al. Angiogenesis and antiangiogenic therapy of colon cancer liver metastasis. Ann Surg Oncol 2003;10:722–33. 4. Takebayashi Y, Aklyama S, Yamada K, Akiba S, Aikou T. Angiogenesis as an unfavorable prognostic factor in human colorectal carcinoma. Cancer 1996;78:226 –31. 5. Vermeulen PB, Van den Eynden GG, Huget P, et al. Prospective study of intratumoral microvessel density, p53 expression and survival in colorectal cancer. Br J Cancer 1999;79:316 –22. 6. Lee JC, Chow NH, Wang ST, Huang SM. Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients. Eur J Cancer 2000;36:748 –53. 7. Shiraishi A, Ishiwata T, Shoji T, Asano G. Expression of PCNA, basic fibroblast growth factor, FGF-receptor and vascular growth factor in adenomas and carcinomas of human colon. Acta Histochem Cytochem 1995;28:21–9. 8. Wong MP, Cheung N, Yuen ST, Leung SY, Chung LP. Vascular endothelial growth factor is up-regulated in the early pre-malignant stage of colorectal tumour progression. Int J Cancer 1999; 81:845–50. 9. Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995;55:3964 – 8.
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