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Department of Medicine (R.M.T., R.J.R.), Endocrinology Service, and Department of Clinical Laboratories (M.F.), Clinical Chemistry Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021; and Department of Pediatrics (G.L.F.), Walter Reed Army Medical Center, Washington, D.C. 20307
Address all correspondence and requests for reprints to: R. Michael Tuttle, M.D., Endocrinology Service, Memorial Sloan-Kettering Cancer Center, Box 419 (H-715), 1275 York Avenue, New York, New York 10021. E-mail: . rmtuttle{at}hotmail.com
Abstract
Solid tumor formation requires the development of a blood supply adequate to meet the metabolic demands of the enlarging tumor mass that cannot be sustained by simple diffusion. One principal stimulant to endothelial cell growth and migration, vascular endothelial growth factor (VEGF), is synthesized and secreted by thyroid cancer cells. Furthermore, VEGF overexpression is associated with an aggressive thyroid cancer phenotype in both animal models and clinical-pathological studies. In other malignancies, elevated serum levels of VEGF often correlate with stage of disease and other poor prognostic clinical features. Therefore, we hypothesized that serum VEGF levels would be significantly higher in patients with persistent or recurrent thyroid cancer than in those cured of the disease. Because TSH stimulates both normal and neoplastic thyroid cells, we also proposed that serum VEGF would be further increased by TSH stimulation. Sixty-nine patients with either papillary or follicular thyroid cancer, status post total thyroidectomy, and prior radioactive iodine ablation, who had undergone routine recombinant human TSH (rhTSH, Thyrogen, Genzyme Transgenics Corp., Cambridge, MA) assisted whole-body radioactive iodine scanning, were included in this study. This cohort (mean age 53 ± 16 yr, 51% female) included 21 patients with no evidence of disease and 48 patients with local or distant metastases. Stored serum samples obtained for standard Tg determinations before and 72 h following standard rhTSH stimulation were identified and assayed for VEGF 165 (R \|[amp ]\| D Systems, Minneapolis, MN). Baseline serum VEGF levels obtained at a time of TSH suppression were significantly higher in patients with known metastatic disease than in those with no evidence of disease (416 ± 62 pg/ml vs. 185 ± 25 pg/ml, P = 0.001). Patients with distant metastases had baseline serum VEGF levels that did not differ significantly from patients with only cervical recurrences (455 ± 90 pg/ml in distant metastases vs. 330 ± 44 pg/ml for local cervical recurrences). Short-term TSH stimulation, although causing a significant rise in serum Tg, resulted in no significant increase in serum VEGF measured 72 h after rhTSH injection in either the patients with known metastatic disease (416 ± 62 pg/ml baseline vs. 419 ± 71 pg/ml after TSH stimulation) or in cured patients (185 ± 25 pg/ml baseline vs. 191 ± 33 pg/ml after TSH stimulation). Subgroup analysis revealed that patients with metastatic disease arising from well differentiated primary thyroid cancers had significantly higher serum VEGF levels than patients with metastatic disease arising from poorly differentiated thyroid cancer primaries (485 ± 74 pg/ml vs. 167 ± 32 pg/ml, P = 0.003 by ANOVA). Poorly differentiated metastatic thyroid cancers had serum VEGF levels indistinguishable from patients cured of disease (167 ± 32 pg/ml vs. 186 ± 25 pg/ml). In summary, serum VEGF is significantly elevated in patients with metastatic differentiated thyroid cancer but not in those with poorly differentiated thyroid cancer metastases. No measurable increase in serum VEGF levels can be detected 72 h after short-term TSH stimulation with rhTSH. We conclude that serum VEGF may serve as a clinical useful marker of residual differentiated thyroid cancer.
SOLID TUMOR GROWTH requires neovascularization to meet the increasing metabolic demands of the enlarging tumor mass. Cancers capable of producing angiogenic factors are at a significant growth advantage because new blood vessel growth enhances the availability of oxygen, glucose, and other nutrients as the tumor achieves a mass too great to be sustained by simple diffusion (1, 2). In thyroid cancer, the relevance of tumor angiogenesis has been demonstrated by significant correlations between microvessel formation and increasing size of the primary tumor (3), intrathyroidal tumor spread (4), and disease-free survival (5).
Vascular endothelial growth factor (VEGF), a principal stimulant to endothelial cell growth and migration, is a 32- to 46-kDa homodimeric glycoprotein that promotes endothelial regeneration, stimulates the formation of collateral blood vessels, increases vascular permeability, and inhibits the function of antigen-presenting cells (6, 7). The VEGF family is composed of several isoforms (VEGF-A, B, C, and D) arising from tissue-specific, alternative splicing of transcripts from a single VEGF gene. VEGF is present in significant quantities in platelets, predominantly as the VEGF-A165 isoform. Specific VEGF transmembrane tyrosine kinase receptors (Flt-1, KDR, Flt-4) are expressed almost exclusively on endothelial cells and mediate downstream intracellular second messenger pathways resulting in endothelial regeneration, stimulation of collateral blood vessel formation, increased vascular permeability, and lymphangiogenesis (8, 9).
Numerous studies have documented abnormal VEGF expression in malignant cells and elevated serum VEGF levels present in patients with a wide variety of malignancies. Serum VEGF levels often correlate with stage of disease and with poor prognostic clinical features (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30).
Human thyroid follicular cells grown in culture can synthesize and secrete VEGF-A in response insulin, phorbol ester, dibutyryl cAMP, TSH, or Graves’ IgG (31, 32, 33). Activation of the TSH receptor by either TSH or Graves’ disease sera has been shown to increase VEGF expression in some (32, 34), but not all (34), thyroid cancer cell lines. Interestingly, TSH stimulation results in significantly more VEGF secretion in thyroid cancer cell lines than in normal cultured thyroid cells (32).
VEGF expression is seldom detected by immunohistochemistry in normal thyroid follicular cells but has been demonstrated in thyroid follicular cells from patients with goiter (35), Graves’ disease (33), subacute thyroiditis (36, 37), and differentiated thyroid cancer (36, 38, 39, 40, 41, 42, 43). Furthermore, increased levels of serum VEGF have been documented in Graves’ patients with large goiters (44). In that study, levels of serum VEGF correlated with ultrasound estimates of vascularity and returned to normal control levels following therapy of Graves’ disease. Furthermore, in hypothyroid subjects, serum VEGF levels correlate with TSH values (44).
A direct association between VEGF expression in thyroid glands and microvessel formation has been recently reported (45, 46). Intense VEGF expression was seen in papillary growth regions showing the highest levels of accumulated microvessels in Graves’ thyroids (45). In a nude mouse dermal matrix model, VEGF levels correlated with the number of blood vessels developed by thyroid cancer xenografts. Furthermore, inhibition of VEGF with a monoclonal antibody resulted in the development of fewer blood vessels (46).
Several reports suggest that expression of VEGF by thyroid cancer cells is associated with a more aggressive phenotype in both animal models and clinical studies (36, 38, 39, 46, 47, 48). In athymic nude mice xenograph models, thyroid cancer cell lines with high VEGF expression are significantly more tumorigenic than cell lines with minimal VEGF expression (47, 48). Growth rates of these VEGF-expressing cell lines are markedly decreased by antibodies specifically directed against the VEGF molecule (46). In clinical studies, overexpression of VEGF by thyroid cancer cells is associated with a higher propensity for both local and distant metastatic spread (36, 38, 39, 40).
On the basis of this large body of information demonstrating the importance of VEGF expression in thyroid cancer, we hypothesized that serum VEGF levels would be significantly higher in patients with persistent or recurrent thyroid cancer than in patients cured of the disease. Furthermore, because TSH stimulates growth of thyroid cancer cells and appears to directly increase VEGF synthesis in preclinical models, we hypothesized that TSH stimulation would increase circulating levels of serum VEGF in patients with persistent or recurrent thyroid cancer but not in patients cured of the disease.
Materials and Methods
Inclusion criteria
Clinical records were retrospectively reviewed to identify all patients with papillary or follicular thyroid cancer who had undergone routine recombinant human TSH (rhTSH, Thyrogen, Genzyme Transgenics Corp., Cambridge, MA) assisted whole-body radioactive iodine scanning in the year 2000. For inclusion in the study, patients had to have had a total or near-total thyroidectomy and radioactive iodine ablation before the current whole body scan, a normal platelet count, and no other known malignancy. If the current rhTSH stimulated whole-body scan showed only thyroid bed uptake (and the patient had no other evidence of persistent or recurrent disease), the patient was excluded because we could not confidently differentiate residual normal thyroid bed activity from persistent thyroid cancer.
Each patient was assigned a clinical status (no evidence of disease or metastatic disease) based on all available clinical data including serum Tg, radioactive scanning, fluorodeoxyglucose positron emission tomography scanning, other standard imaging procedures, and cytologic or histologic biopsy specimens. Patients with stimulated serum Tg values greater than or equal to 2 ng/ml during TSH suppression were classified as having persistent disease. The metastatic disease category included patients with local or distant metastases from either persistent or recurrent thyroid cancer. Histology classification was based on the original pathology report and any other available tissue samples obtained at the time of recurrence. The histology was classified as poorly differentiated if the primary tumor or recurrence contained significant areas of poorly differentiated cytoarchitecture.
Serum samples
Blood samples used in this study were obtained as part of routine clinical evaluations for serum Tg measured both during baseline thyroid hormone suppression just before rhTSH stimulation and 72 h following rhTSH stimulation as previously described (49). The blood samples were initially processed for serum Tg measurements and subsequently stored at -70 C. The baseline sample was obtained on d 1 (TSH suppressed on levothyroxine, before rhTSH administration). The TSH-stimulated blood sample was collected 72 h following the second of two consecutive daily 0.9-mg im injections of rhTSH.
Serum VEGF measurements
Serum VEGF measurements were performed in batches using the Quantikine human VEGF sandwich enzyme immunoassay (R&D Systems, Minneapolis, MN) after 1–3 months of storage time at -70 C. A murine monoclonal antibody against VEGF 165 was used as the capture antibody and a polyclonal antibody conjugated with horseradish peroxidase as the reporting antibody at 450 nm. The VEGF assay was calibrated against a highly purified recombinant human VEGF 165. In addition to detecting VEGF 165, the assay cross-reacts with VEGF 121 on an equimolar basis. Interassay coefficients of variation ranged from 6.0–7.0% over the concentration range of 65 to 1000 pg/ml. All assays were performed in duplicate.
Validation of the serum VEGF assay included measurements on 31 individual blood samples obtained from healthy adult blood donors. These subjects are presumed to be healthy and free of malignancy based on the information provided by the subject at the time of blood donation. The mean VEGF concentration in this normal control group was 216 ± 132 pg/ml. The normal reference range (±2 SD around the mean) was established to be 0–480 pg/ml.
Serum Tg measurements
Serum Tg was measured with an IRMA assay (Dynotest Tg S, Brahms, Berlin, Germany) that uses Tg recovery (50 ng/ml) to detect interference by autoantibodies and has a low end sensitivity of 0.3 ng/ml.
Statistical analysis
All data are presented as the mean ± SEM with medians when appropriate. Statistical analysis was performed using SPSS for Windows (SPSS, Inc., Chicago, IL). Mean values were compared using independent sample t test, paired-samples t test, or ANOVA as appropriate. Comparison of categorical data was performed using the 
2 test (Fisher’s exact). A P value less than 0.05 was considered significant.
Results
Baseline samples were available from 69 patients meeting our study criteria. Paired samples (baseline and TSH stimulated) were available in 63 of these patients. For the entire cohort, the mean age at diagnosis of thyroid cancer was 47 ± 16 yr with a mean age at the time of the study of 53 ± 16 yr. Thirty patients (51%) were female. Histological classification of the tumors revealed 37 classic papillary cancers (54%), 16 follicular variant of papillary cancers (23%), 5 classic follicular cancers (7%), and 11 papillary cancers with significant areas of poorly differentiated features (16%).
Twenty-one patients (30%) were classified as no evidence of disease at the time of VEGF determination, and 48 (70%) had evidence of metastatic disease. Isolated cervical disease was present in 15, and distant metastases were present in the remaining 33 patients (including 10 with cervical and lung metastases, 9 with only lung metastases, 4 with only bone metastases, and 10 with multiple combinations of distant metastatic sites).
Baseline serum VEGF levels obtained at the time of TSH suppression were significantly higher in patients with known metastatic disease than in those classified as no evidence of disease (416 ± 62 pg/ml vs. 185 ± 25 pg/ml, P = 0.001). All patients with no evidence of disease had serum VEGF levels within the normal range for serum VEGF established in healthy control subjects.
In patients with metastatic disease, rhTSH stimulation resulted in the expected significant rise in serum Tg from a baseline of 504 ± 154 mIU/ml (median value 13 mIU/ml) to a stimulated value of 1488 ± 386 mIU/ml (median value 90 mIU/ml, P < 0.0001). However, short-term TSH stimulation resulted in no significant increase in serum VEGF measured 72 h after rhTSH injection in either the patients with known metastatic disease (416 ± 62 pg/ml baseline vs. 419 ± 71 pg/ml after TSH stimulation) or in cured patients (185 ± 25 pg/ml baseline vs. 191 ± 33 pg/ml after TSH stimulation) (Fig. 1
). As expected, rhTSH stimulation resulted in no significant change in serum Tg in patients with no evidence of disease (baseline-suppressed Tg was 0.3 ± 0.1 ng/ml and the stimulated Tg value was 0.4 ± 0.3 ng/ml).
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Analysis of serum VEGF levels based on the presence of fluorodeoxyglucose-avid lesions by positron emission tomography scanning failed to reveal any significant differences (data not shown). Furthermore, the percent change in stimulated serum VEGF from baseline was not significantly different when analyzed either by clinical status or histologic classification. Finally, there was no significant correlation between baseline serum VEGF levels and either suppressed or stimulated Tg measurements (data not shown).
Discussion
Patients with metastatic thyroid cancer have significantly higher levels of serum VEGF than patients who are apparently cured of the disease. Although nonthyroidal sources of VEGF (such as platelets) are responsible for the baseline serum VEGF levels measured in all subjects, the higher serum VEGF levels in the metastatic patients argues that the thyroid cancer cells are likely the source of the serum VEGF. Furthermore, the presence of VEGF by immunohistochemistry in clinical thyroid cancer samples and the documentation of VEGF synthesis and secretion in thyroid cell culture systems supports the hypothesis that thyroid cancer tissue is the source of the increased serum levels of VEGF seen in metastatic thyroid cancer patients (31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43). This clinical study supports the hypothesis that VEGF-stimulated angiogenesis is important in the progression of papillary thyroid cancer (2).
Several studies have demonstrated that platelets are rich in VEGF (18, 50, 51). In fact, plasma VEGF levels meticulously collected to avoid platelet disruption demonstrate significantly lower VEGF levels than simultaneously collected serum samples (50, 52). It seems unlikely that platelet lysis significantly influenced our results because each subject had samples obtained on two different days, which were processed independently. The minor variation between these two samples indicated that inadvertent platelet disruption is not likely to account for the differences detected in this study.
Our findings add thyroid cancer to a long list of solid tumors in which serum VEGF levels are elevated and may serve as a marker of persistent or recurrent disease (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30). However, because VEGF expression is not restricted to the thyroid, an elevation in serum VEGF will be a much less specific indicator of thyroid cancer recurrence than Tg. Prospective clinical studies will be required before an assessment can be made regarding the clinical utility of the serum VEGF assay in papillary thyroid cancer survivors.
In other malignancies, the level of serum VEGF has been shown to correlate with stage of disease, volume of disease, and differentiation status of the tumor (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30). Even though there was no statistical correlation between serum VEGF levels and stage of disease at diagnosis, the highest serum VEGF levels measured in this study were seen in patients with widespread, large-volume distant metastases from well-differentiated thyroid cancers.
The low level of serum VEGF detected in the poorly differentiated papillary thyroid cancers was quite unexpected. Because these histologies usually have a more aggressive clinical behavior, high levels of VEGF expression would have been expected based on the preclinical animal and cell culture data. De-differentiation in thyroid cancer is often association with a decline in loss of function of other important proteins including Tg and sodium iodine symporter (53, 54). Therefore, the lack of an elevated serum VEGF in poorly differentiated thyroid cancers is consistent with a loss of synthesis, secretion, or function of several other important complex proteins within the thyroid cell. The angiogenic stimulus to these poorly differentiated papillary thyroid cancers may be one of the alternative forms of VEGF that may not be detected in our assay or one of the numerous other angiogenic factors recently described (2).
Unlike the response reported in cell culture systems (31, 32, 33), short-term TSH stimulation failed to cause a significant increase in serum VEGF. The time point for measurement of serum VEGF following TSH stimulation was selected to correspond to the time of maximal Tg response to TSH stimulation. Therefore, we cannot rule out a more rapid or delayed effect of TSH on VEFG synthesis and secretion. It is also possible that the TSH stimulation did result in an increase in synthesis and secretion of VEGF within the tumors without a rise in serum VEGF. However, it seems likely that the response of VEGF stimulation and secretion in response to TSH stimulation and cAMP stimulation are unique to thyroid cell culture lines and are not uniformly present in papillary thyroid cancers in vivo (31, 32, 33, 34). Further studies will be needed to elucidate the precise mechanisms involved.
Unlike malignant thyrocytes, the elevation of serum VEGF in response to long-term TSH receptor stimulation in Graves’ disease and in primary hypothyroidism suggests that nonmalignant thyroid cells in vivo are capable of both VEGF synthesis and secretion (44).
Because metastatic thyroid cancers appear to synthesize and secrete VEGF, it is reasonable to hypothesize that this molecule is important for development and progression of these metastatic sites. If this is correct, interruption of the VEGF signaling system should have negative effects of tumor growth and viability. Interestingly, recent work has demonstrated that ip injection of anti-VEGF antibody is associated with a marked growth inhibition of thyroid cancer xenographs in nude mice (55). Furthermore, several compounds that inhibit VEGF activity are currently in early clinical trials (56, 57). Thyroid cancer patients with high levels of serum VEGF would appear to be an excellent initial cohort to examine the effects of anti-VEGF therapies.
In conclusion, serum VEGF is significantly elevated in patients with metastatic differentiated thyroid cancer but not in patients with poorly differentiated thyroid cancer metastases. No measurable increase in serum VEGF levels can be detected 72 h after short-term TSH stimulation with rhTSH. Serum VEGF may serve as a marker for persistent/recurrent differentiated thyroid cancer and is an important potential therapeutic target for novel treatment approaches.
Acknowledgments
Footnotes
This work was supported in part by a grant from the Byrne Fund, Memorial Sloan Kettering Cancer Center (to R.M.T.).
Abbreviations: rhTSH, Recombinant human TSH; VEGF, vascular endothelial growth factor.
Received August 13, 2001.
Accepted December 24, 2001.
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