Original Article
Transforming Growth Factor β as a Predictor of Liver and Lung Fibrosis after Autologous Bone Marrow Transplantation for Advanced Breast Cancer
N Engl J Med 1993; 328:1592-1598June 3, 1993
- Abstract
Background
Hepatic veno-occlusive disease and idiopathic interstitial pneumonitis are major causes of morbidity and mortality after bone marrow transplantation. Fibrosis is a characteristic of both conditions, and transforming growth factor β (TGFβ) has been implicated in the pathogenesis of fibrosis.
Methods
Using acid-ethanol extraction to remove TGFβ from human plasma and a mink-lung epithelial-cell growth-inhibition assay to measure TGFβ activity, we quantified plasma TGFβ in 10 normal subjects and 41 patients before and after they underwent high-dose chemotherapy and autologous bone marrow transplantation for advanced breast cancer.
Results
There was no difference in pretransplantation TGFβ levels between the controls and the patients who did not have hepatic veno-occlusive disease or idiopathic interstitial pneumonitis after transplantation. In contrast, pretransplantation TGFβ levels were significantly higher in patients in whom hepatic veno-occlusive disease or idiopathic interstitial pneumonitis developed than in the controls or the patients without these conditions. The predictive value for the development of either condition was 90 percent or more when pretransplantation plasma TGFβ levels were more than 2 SD above the mean established in the controls.
Conclusions
The plasma TGFβ concentration measured after induction chemotherapy but before high-dose chemotherapy and autologous bone marrow transplantation strongly correlates with the risk of hepatic veno-occlusive disease and idiopathic interstitial pneumonitis after these treatments.
Media in This Article
Figure 1
Treatment Protocol and Plasma Sampling in 102 Women with Breast Cancer.Figure 2
Individual TGFβ Plasma Concentrations in the Four Study Groups.Article Activity
- Article
Hepatic veno-occlusive disease is a serious consequence of high-dose chemotherapy or radiotherapy combined with bone marrow transplantation for neoplasia; it occurs in 15 to 50 percent of patients, with a mortality rate of up to 50 percent1-7. The syndrome typically develops one to three weeks after transplantation and is characterized by sudden weight gain, hepatomegaly, ascites, and hyperbilirubinemia7; hepatic encephalopathy may also develop.
Similarly, pulmonary complications of bone marrow-transplantation are a major source of morbidity, occurring in 40 to 60 percent of patients8. Noninfectious pulmonary complications (idiopathic interstitial pneumonitis) occur in 10 to 25 percent of bone marrow-transplant recipients8. This syndrome is characterized by dyspnea, fever, and hypoxemia, with or without diffuse interstitial infiltrates on chest radiography. It occurs 40 to 75 days after transplantation; the mortality rates are high. Both the chemotherapy and the radiotherapy used in the conditioning regimens have been implicated in the development of liver and lung damage after bone marrow transplantation1,8,9.
Fibrosis is a prominent feature in both the lungs and the liver in patients with these complications10,11. Recently, efforts have been directed at elucidating the molecular mechanisms of these fibrotic reactions. Transforming growth factor β (TGFβ) stimulates fibroblasts to migrate to the site of injury, proliferate, and produce collagen; it also inhibits collagen degradation12. Thus, it plays an important part in normal wound healing13,14 as well as in abnormal fibrogenesis. TGFβ has been implicated in the causation of chronic pulmonary fibrosis in rats and mice exposed to bleomycin or cyclophosphamide15-20 and in the development of hepatic fibrosis in rats exposed to radiation21 or carbon tetrachloride22,23. TGFβ may also have a role in fibrotic liver and lung diseases in humans,24-27 such as chronic hepatitis,28 idiopathic pulmonary fibrosis,29,30 and systemic sclerosis31-33. Inhibition of TGFβ activity can prevent the development of chronic hepatitis,28 acute mesangial proliferative glomerulonephritis,34 and the cirrhotic effects of carbon tetrachloride,35 providing further evidence for the role of TGFβ in these fibrotic conditions.
Because the level of expression of the gene for TGFβ1 is elevated in both animals and humans with fibrotic liver or lung diseases,28,30 we postulated that an increase in the release and activation of TGFβ1 in fibrotic tissue would also result in an increase in the circulating level of this growth factor. It may be possible to use the plasma concentration of TGFβ proteins measured before the administration of high-dose chemotherapy to identify patients most prone to the development of lung or liver injury after bone marrow transplantation.
Methods
Patients
At the time of this analysis, 102 women with adenocarcinoma of the breast had been treated according to research protocols for bone marrow transplantation at Duke University Medical Center. All patients had either stage IV disease (metastases) or advanced stage II or III disease (more than 10 positive lymph nodes found after axillary dissection) and underwent four cycles of induction chemotherapy followed by high-dose chemotherapy and autologous bone marrow transplantation (Figure 1Figure 1
Treatment Protocol and Plasma Sampling in 102 Women with Breast Cancer.). The details of this treatment regimen have been previously reported36. In brief, the induction regimen consisted of cyclophosphamide, doxorubicin (Adriamycin), and fluorouracil (for stage II or III disease) or doxorubicin, fluorouracil, and methotrexate (for stage IV disease). The high-dose chemotherapy consisted of carmustine, cyclophosphamide, and cisplatin. Radiation therapy was directed at the sites of known metastases (stage IV disease) or to the ipsilateral chest wall, internal mammary nodes, and supraclavicular lymph nodes (stage II or III disease) after autologous bone marrow transplantation.Of the 102 patients treated, 12 subsequently had hepatic veno-occlusive disease, 19 had pulmonary fibrosis, and the remaining 71 had neither. Both conditions were defined clinically. Hepatic veno-occlusive disease was indicated by the development of weight gain, hepatomegaly, ascites, and hyperbilirubinemia one to three weeks after transplantation. Pulmonary fibrosis was indicated by dyspnea, fever, and hypoxemia with or without diffuse interstitial infiltrates on chest radiography, beginning 40 to 75 days after transplantation. Other causes of these two syndromes had to be excluded in order to accept these diagnoses. Biopsy was not required. All patients with hepatic veno-occlusive disease or pulmonary fibrosis were included in this analysis. A sample of 10 patients who had neither condition (a sample matching the number of controls, described below) was randomly selected from among all patients enrolled under these protocols whose plasma samples were stored in the archives of the cryopreservation laboratory. Specimens were coded, and TGFβ levels measured, without the investigators' prior knowledge of whether or not the patient had hepatic veno-occlusive disease or pulmonary fibrosis. After the plasma TGFβ levels in the samples were measured, the code was broken and the data were grouped for analysis according to the patients' status for toxic complications (see below).
Plasma samples were obtained twice. The first sample was obtained after induction chemotherapy but before the administration of high-dose chemotherapy and autologous bone marrow transplantation. The second sample was obtained after the high-dose chemotherapy and transplantation (Figure 1), between 12 and 37 days after the operation, depending on the availability of adequate samples. The findings in the transplant recipients were compared with those in controls -- 10 normal blood donors whose plasma was obtained from the American Red Cross (Charlotte, N.C.).
Extraction of TGFβ from Plasma
Total TGFβ (both active and inactive forms) was isolated from the plasma through acid-ethanol extraction37,38. Because this extraction procedure activates TGFβ, we could not determine the amount of active and inactive TGFβ present in the samples. To extract TGFβ, 4 ml of an acid-ethanol solution (375 ml of 95 percent ethanol, 7.5 ml of 12 N hydrochloric acid, 33 mg of phenylmethylsulfanylfluoride, and 1.9 mg of pepstatin) was added to a 1-ml plasma sample previously diluted by a factor of 2 with distilled water. The samples were incubated overnight at 4 °C, then centrifuged at 20,000 × g for 30 minutes at 4 °C. The supernatant was removed and stored at 4 °C, and the remainder of the sample was reextracted and centrifuged. The two supernatants were then combined, and the pH was adjusted to 5.2 to 5.3 with ammonium hydroxide. One milliliter of 2 M ammonium hydroxide was added to 85 ml of supernatant and diluted by a factor of 3 with cold (4 °C) 100 percent ethanol. This solution was incubated at -20 °C for at least two days and then centrifuged. The pellet was resuspended in 4 ml of 1 M acetic acid, dialyzed overnight in 1 percent acetic acid, divided into aliquots, lyophilized, and stored at -20 °C.
Assay for TGFβ
Plasma levels of TGFβ were quantified with the use of an assay measuring the inhibition of the growth of mink-lung epithelial cells39. Because this assay is not capable of discriminating among the three isoforms of TGFβ, throughout this paper we simply use the term “TGFβ.” In brief, after the MV 1 Lu mink-lung epithelial cells (CCL-64) were subjected to trypsinization and suspended in the assay medium, they were plated at a concentration of 105 cells per milliliter. After incubation at 37 °C for 1 hour, TGFβ test samples and standards of known TGFβ1 concentration were added to the wells and incubated at 37 °C for 22 hours. The extent of DNA synthesis was then determined by incubating the cells with 3H-labeled thymidine at 37 °C for an additional four hours. The cells were finally fixed for one hour at room temperature in 1.0 ml of methanol-acetic acid solution (3:1 vol/vol) and washed twice in 80 percent methanol. They were then solubilized in 0.3 N sodium hydroxide, and the radiolabeled DNA was extracted by precipitation with trichloroacetic acid. The amount of radioactivity in the cells exposed to the test samples and TGFβ1 standards was determined with a liquid-scintillation counter. This assay was able to detect amounts of TGFβ ranging from 0.05 to 0.5 ng per milliliter (0.2 to 2 × 10-8 mmol per liter), with 50 percent inhibition occurring at a concentration of 0.1 ng per milliliter (0.4 × 10-8 mmol per liter). The samples were serially diluted until the quantities of TGFβ present were in the linear portion of the sigmoid-shaped curve for the TGFβ standard. Actual TGFβ levels were then calculated by multiplying the measured TGFβ concentration by the dilution factor. Test samples were always assayed with samples containing known quantities of TGFβ to ensure the reliability of the bioassay.
To determine whether the inhibitory effect of the test samples was due specifically to TGFβ, a neutralizing antibody that recognized TGFβ (R&D Systems, Minneapolis) was added to all the test samples one hour before they were added to the mink-lung cells. Because the antibody was not specific for an individual isoform of TGFβ, we could not determine the relative contributions of the three isoforms to the total plasma concentration. In all test samples the TGFβ antibody was able to neutralize completely the inhibition of 50 percent of the cell growth (data not shown).
Statistical Analysis
Plasma TGFβ was measured in the controls and patients both before and after bone marrow transplantation. Analysis of variance and Scheffe's method of multiple comparisons were used to compare mean values determined before and after transplantation in patients according to whether they subsequently had hepatic veno-occlusive disease, pulmonary fibrosis, or neither condition. Sensitivity, specificity, and predictive values (positive and negative) were calculated on the basis of a cutoff value for plasma TGFβ of 10 ng per milliliter (4 × 10-7 mmol per liter), which was 2 SD above the mean determined in the controls (6 ng per milliliter [2.4 × 10-7 mmol per liter]).
The clinical variables determined in each patient are shown in Table 1Table 1
Clinical Characteristics Evaluated in 102 Women with Breast Cancer.. These data were analyzed in the same way as the TGFβ measurements40. No clinical information was available for the controls because they were anonymous blood donors. Laboratory values were measured on or as close as possible to the dates on which plasma samples were obtained for measurement of TGFβ (Figure 1), to determine whether there were any differences between the patients in whom hepatic veno-occlusive disease or pulmonary fibrosis developed and the patients without these complications.Results
The characteristics of the 41 patients who underwent autologous bone marrow transplantation for advanced breast cancer are shown in Table 2Table 2
Characteristics of Patients Undergoing Autologous Bone Marrow Transplantation for Breast Cancer.. The patients in whom pulmonary fibrosis or hepatic veno-occlusive disease later developed and the patients without these complications were similar in all respects except that the group with hepatic veno-occlusive disease included patients with distant metastases who had received chemotherapy or radiotherapy before they were enrolled in the transplantation program. The mortality rates for pulmonary fibrosis and hepatic veno-occlusive disease were 26 percent and 17 percent, respectively (Table 2).The TGFβ concentrations in each patient and control are shown in Figure 2Figure 2
Individual TGFβ Plasma Concentrations in the Four Study Groups.; the solid line at 10 ng per milliliter represents the TGFβ level 2 SD above the mean value of 6.1 ng per milliliter (2.4 × 10-7 mmol per liter) determined in the controls (10 healthy blood donors). The mean TGFβ concentrations in each study group are shown in Figure 3Figure 3
Mean (±SEM) TGFβ Concentrations in the Controls and Patients.. When we compared the TGFβ levels measured in the patients before transplantation with the levels in the controls, we found no significant difference (P>0.1) between the controls and the patients who did not have hepatic veno-occlusive disease or pulmonary fibrosis after transplantation. In contrast, the pretransplantation TGFβ levels in patients who later had hepatic veno-occlusive disease or pulmonary fibrosis were significantly higher (P = 0.003) than those in the controls and the patients without fibrotic changes in their lungs or liver.After autologous bone marrow transplantation, there was a significant decrease (P<0.001) in the TGFβ levels of patients with subsequent hepatic veno-occlusive disease or pulmonary fibrosis (Figure 2 and Figure 3). This decrease paralleled a marked decrease in the platelet count after the high-dose chemotherapy (Table 3Table 3
Mean (±SEM) TGFβ Levels and Platelet Counts before and after Autologous Bone Marrow Transplantation.). In contrast, the plasma TGFβ levels remained unchanged (P>0.1) in the patients who did not have hepatic veno-occlusive disease or pulmonary fibrosis, even though their platelet counts decreased to the same extent as the counts of the patients who did have these complications. Although there was a significant difference in pretransplantation TGFβ levels between the groups with hepatic veno-occlusive disease and pulmonary fibrosis and the group without these developments, as noted above, there was no significant (P>0.1) difference in the post-transplantation levels among these three groups.To test the usefulness of the TGFβ level as an indicator of an increased risk of hepatic veno-occlusive disease or pulmonary fibrosis after high-dose chemotherapy and autologous bone marrow transplantation, the sensitivity, specificity, and the positive and negative predictive values of this marker were calculated. To make these calculations, the upper limit of normal TGFβ levels in plasma was set at 10 ng per milliliter, which was 2 SD above the mean value in normal subjects (Figure 2). The resulting values (Table 4Table 4
Pretransplantation Measurement of Plasma TGFβ as a Predictor of Liver and Lung Fibrosis after High-Dose Chemotherapy and Autologous Bone Marrow Transplantation.) showed that the TGFβ level measured in plasma after induction chemotherapy but before high-dose chemotherapy and transplantation was a very good indicator of which patients would subsequently have pulmonary fibrosis or hepatic veno-occlusive disease (or both) after chemotherapy and transplantation. If the plasma concentration of TGFβ was greater than 10 ng per milliliter, it was possible to predict with more than 90 percent accuracy that either hepatic veno-occlusive disease or pulmonary fibrosis would develop (i.e., the positive predictive value was >90 percent).We also attempted to determine whether the development of pulmonary fibrosis or hepatic veno-occlusive disease was associated with any of the variables listed in Table 1. We could find no significant difference in the mean values for these clinical factors between the patients with these complications after transplantation and those without them (P>0.1 in all cases). Furthermore, there was no correlation between any of the factors and the pretransplantation TGFβ levels in the three groups of patients (data not shown).
To explore the possibility that TGFβ might be produced by the tumor, the relation between tumor burden, as measured by the maximal tumor dimension and the number of lymph nodes involved by cancer, and the plasma TGFβ concentration before transplantation was determined (Table 5Table 5
TGF(β) Concentration in Relation to Tumor Burden in Patients with Liver or Lung Fibrosis.). There were no significant differences in pretransplantation TGFβ levels when the patients were compared according to the number of involved lymph nodes or the greatest measurable tumor dimension (before induction chemotherapy).We also considered the possibility that patients with stage IV cancer who had previously received chemotherapy (before their enrollment in the bone marrow transplantation study) might be at increased risk for toxic complications, as compared with patients who had not previously received chemotherapy. This comparison could be made only in the group with hepatic veno-occlusive disease, since no patient in the other groups had been previously treated with chemotherapy. We found no difference (P>0.1) in the pretransplantation TGFβ levels between the patients who had received previous chemotherapy and those who had not, which suggested that previous chemotherapy did not necessarily increase the risk of hepatic veno-occlusive disease in this group.
Discussion
Hepatic veno-occlusive disease and pulmonary fibrosis are major causes of morbidity and mortality after bone marrow transplantation for cancer. Many clinical factors define patient populations at increased risk for the development of these complications,1,2,41-46 but none of these clinical factors have been useful in assessing the risk in an individual patient. Our study indicates that the plasma TGFβ concentration, if measured after induction chemotherapy, strongly correlates with the development of pulmonary fibrosis or hepatic veno-occlusive disease after high-dose chemotherapy and autologous bone marrow transplantation.
Patients most prone to pulmonary fibrosis or hepatic veno-occlusive disease after high-dose chemotherapy and autologous bone marrow transplantation have elevated TGFβ levels before transplantation. A positive test for TGFβ has a positive predictive value of more than 90 percent for the development of either hepatic veno-occlusive disease or pulmonary fibrosis in a given patient. It may be possible to use TGFβ plasma levels to individualize therapy and thus reduce the risk of both complications.
We chose the assay system we used in this study because of its ability to detect very low levels of TGFβ. Although enzyme-linked immunosorbent assays for the quantification of TGFb47 are less sensitive than our biologic assay, our results demonstrate that enzyme-linked immunosorbent assays should have sufficient sensitivity to permit rapid screening for patients most prone to fibrotic changes (i.e., patients with plasma levels of TGFβ1 above 10 mg per milliliter [4 × 10-7 mmol per liter]).
The cause of elevated plasma levels of TGFβ in patients who ultimately have hepatic or pulmonary fibrosis is not known. Platelets are the principal source of TGFβ in humans, but an artifactual disruption of platelets seems unlikely. For TGFβ levels to become falsely elevated in the patients we studied, blood samples would have had to have been obtained shortly after platelet destruction occurred, since the half-life of TGFβ in the blood is only a few minutes. Also, the putative destruction of platelets by drugs or venipuncture would have had to have occurred only in the patients who ultimately had fibrosis. Finally, all patients treated with high-dose chemotherapy and autologous bone marrow transplantation had a decrease in TGFβ concurrent with chemotherapy-induced thrombocytopenia.
The elevation of plasma levels of TGFβ in patients with hepatic veno-occlusive disease or pulmonary fibrosis also does not appear to be related to their tumor burden. Some factor other than the tumor is apparently responsible for the elevated TGFβ levels in patients with these complications.
Increased synthesis or activation of TGFβ or decreased degradation of this growth factor (or some combination of these processes) is a possible response to induction chemotherapy in patients who subsequently have hepatic veno-occlusive disease or pulmonary fibrosis. Hoyt and Lazo20 have shown that strain-specific variations in TGFβ messenger RNA in the lungs of mice correlate with differences in susceptibility to cyclophosphamide-induced pulmonary fibrosis. Genetic differences may also occur in human responses to chemotherapeutic agents.
TGFβ is normally secreted from cells as a glycosylated latent complex that contains phosphorylated mannose residues48. It must be dissociated from this complex to become biologically active. The latent complex of TGFβ1 binds to the receptor that accepts both glycoproteins containing mannose-6-phosphate and insulin-like growth factor II,49 and this binding has been shown to facilitate the activation of the TGFβ1 molecule by proteolytic enzymes19. It is possible that this activation process is augmented in patients in whom hepatic veno-occlusive disease or pulmonary fibrosis develops, and consequently more mature TGFβ would be present in the plasma. We have observed an increased concentration of TGFβ in hepatocytes with increased numbers of mannose-6-phosphate-insulin-like growth factor II receptors when the liver is undergoing regeneration50 or has been exposed to the liver-tumor promoter phenobarbital51. Whether a concomitant increase in the level of TGFβ1 and the number of mannose-6-phosphate-insulin-like growth factor II receptors also occurs in the liver and lungs of humans after exposure to chemotherapeutic agents, radiation, or other insults resulting in fibrosis is unknown.
Supported by grants (CA-40172 and CA-25951) from the National Cancer Institute.
We are indebted to Karen Hillary for technical assistance, to Denise Crawford for assistance in data acquisition, to Richard Dodge for statistical advice, and to Roxanne Scroggs for assistance in the preparation of the manuscript.
Source Information
From the Department of Radiation Oncology (M.S.A., H.R., R.L.J.) and the Department of Medicine, Division of Hematology-Oncology (W.P. Peters, W.P. Petros), Duke University Medical School, Durham, N.C.
Address reprint requests to Dr. Jirtle at Box 3433, Duke University Medical Center, Durham, NC 27710.
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