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Serum-hepatocyte Growth Factor (S-HGF) in Diagnosis of SPNs

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Value of hepatocyte growth factor in the differential diagnosis of solitary pulmonary nodules[F1]

Haixin Yu, Yan Wang*, Wenduan Ma, Haixiang Yu, Shengtao Shang

Abstract

Purpose: To evaluate serum-hepatocyte growth factor (S-HGF) in the differentiation of solitary pulmonary nodules(SPNs)[F2].[F3]

Methods: The study comprised 42 serum samples from SPN patients and 10 healthy samples as control. The HGF was measured by the commercially available immunoassay[F4].[F5] Serum levels of HGF of 42 patients with SPN was measured by ELISA kit, and compared with the control group of 10 normal subjects. The nodules were diagnosed by operation and pathology.

Results: The median level of S-HGF was 180( range from 100 to 300) pg/ ml in the healthy control group, 165( range from 100 to 400) pg/ ml in benign SPNs group and while 395( range from 100 to 1550) pg/ ml in malignant SPNs group, The S-HGF mean level of malignant group was significantly higher than the with significant difference observed between the malignant group and control group(P<0.05). Moreover, the malignant group was also significantly higher than the , and between the malignant group and the benign group(P<0.05) while no significant difference between the benign , but not between the benign group and the control group(P>0.05). Furthermore, the S-HGF was also shown no statistically significant difference was observed(P>0.05) in different pathologic types of the limited number of lung cancer patients.In addition, when S-HGF in different pathologic types of the limited number of lung cancer patients were compared, no statistically significant difference was observed(P>0.05).

Conclusion: S-HGF is valuable in the differential diagnosis of solitary pulmonary nodules. It was suggest that the patients with SPNs should consider an operation when the S-HGF level 250pg/ml, and malignant SPNs are highly suspected while S-HGF level ≥400pg/ml, surgical intervention should be taken immediately.S-HGF is valuable in the differential diagnosis of solitary pulmonary nodules. An elevated S-HGF level≥250pg/ml in patients with SPNs may strongly speak for malignant nodules and operation is suggested. If S-HGF level ≥400pg/ml, malignant SPNs are highly suspected, active surgical intervention should be taken.

Key words: diagnosis, hepatocyte growth factor, solitary pulmonary nodule, NSCLClung cancer

1.Introduction

The solitary pulmonary nodules (SPNs) is a single mass in the lung less than or equal to 3 cm in diameter, without concomitant pneumonia and atelectasis of involved lung segments and lobes [1]. In the general population, it’s reported that approximately 5% of SPN patients show lung cancer by radiology [2], which is considered one of the most common forms of cancer with a high death incidence ratio in the world [3]. Diagnoses of benign and malignant SPN has been concerned and become a challenge in these decades [4, 5]. Therefore, it is utmost important to improve the method in the characterization of SPNs[6]. [张英彪6]

With the development of modern medical science and technology, several detecting and monitoring method were used in screening the SPNs and lung cancer [2, 7, 8], Momen[9] et al. have compared three detection methods for identifying malignant SPNs for the sensitivity and specificity. The positron emission tomography (PET) imaging was consistently higher (80 to 100%) for its sensitivity, while was with lower specificity and larger variation (40 to 100%). Also, they found the similar results in dynamic CT with enhancement (sensitivity, 98 to 100%; specificity, 54 to 93%). In studies of CT-guided needle biopsy, sensitivity and specificity performed excellent, but nondiagnostic results were seen approximately 20%. Dalli[8] et al. also showed the similar result in 2013. While Carsten[10] et al. suggested that routine flexible bronchoscopy should be included in the pre-operative work-up of patients with SPNs in his study. Even so, it seems to find a better detection method of long cancer and characterization of SPNs is still necessary.[张英彪7]

Serum-hepatocyte growth factor (S-HGF, Serum-HGF) is an important fibroblast-secreted protein that mediates development and progression of cancers[11]. Nagio et al. [12] gave the evidence that the S-HGF levels of patients with small cell lung cancer (SCLC) were significantly higher than those of patients with benign SPNs and healthy subjects. Ujiie et al[13] had proved that the levels of HGF in serum could be used as prognostic indicators of the patients with stage III non-small cell lung cancer (NSCLC) undergoing surgery and chemotherapy. Kasahara et al. [14] found that higher HGF levels were significantly associated with a shorter progression-free survival (PFS) and overall survival (OS) in patients with non-small cell lung adenocarcinoma. The expression level of S-HGF could be a sensitive indicator and an independent biomarker for evaluating the therapeutic effects and the prognosis in patients with lung cancer. Therefore, we give the hypothesis that S-HGF may be a potential target in diagnoses of benign and malignant SPNs associated with lung cancer. In our study, we used Enzyme linked immunospot assay (ELISA) method to detect the S-HGF levels between different serum samples from SPNs patients and healthy subjects.[张英彪8]The solitary pulmonary nodule(SPN) is defined as a round opacity ≤3 cm in diameter surrounded by lung parenchyma[1].There should be no associated with hilar lymphadenopathy, atelectasis, pneumonia or chest wall pathologies. With more importance attached to physical examination and the development of medical imaging examination technology, the detection rate of SPN is on the increase.

In the general population, approximately 5% of all SPNs shown by radiology are reported to be carcinomas[2]. In eight large trials of lung cancer screening, Momen et al[3] have compared the sensitivity and specificity in three detection methods for identifying malignant SPNs. The sensitivity of PET imaging was consistently high (80 to 100%), whereas specificity was lower and more variable (40 to 100%). They found similar results in dynamic CT with enhancement(sensitivity, 98 to 100%; specificity, 54 to 93%).In studies of CT-guided needle biopsy, sensitivity and specificity were excellent, but nondiagnostic results were seen approximately 20% of the time. Carsten et al[4], in a study of 225 patients with SPN of unknown origin, observed that the bronchoscopic biopsy results were positive in 84(46.5%) patients with lung cancer. The differential diagnosis between malignant and benign solitary pulmonary nodules (SPNs) is always a difficult point in clinical practice. In this study, we investigate the clinical significance of the serum level of hepatocyte growth factor(HGF) in patients with SPNs.

2. Methods

2.1. Patients

According to the definition, inclusion criteria was set:(1)On computed tomography (CT), SPN is a round opacity ≤3 cm in diameter surrounded by lung parenchyma.(2)There should be no associated with hilar lymphadenopathy, atelectasis, pneumonia or chest wall pathologies.(3)Regardless of age and gender. In consideration of some influences, exclusion criteria was set:(1)Inflammation or infection within a month. (2)Surgery or trauma within 6 months. (3)Various liver diseases. (4)Chronic renal failure. (5)Arteriosclerosis. (6)Rheumatoid arthritis and osteoarthritis. (7)Diabetes mellitus.

The case group included 42 patients with SPNs, mean age 60.7 years (range, 42 to 72). Besides, 10 healthy adult subjects were chosen as control.

2.2. Specimen collection

The morning fasting venous blood of all subjects was collected in sterile polypropylene tubes, containing ethylenediamine tetraacetic acid (EDTA), and immediately centrifuged at 400rpm for 10min. Then, the plasma was stored at -70°C until the assays were performed.

2.3. Assay for S-HGF

We used Sandwich enzyme-linked immunosorbent assay(ELISA) to measure S-HGF. The HGF monoclonal antibody and standard substance for the assays were purchased from American R&D systems. Goat-anti-human HGF polyclonal antibody as the primary antibody and donkey-anti-goat IgG polyclonal antibody labeled with horseradish peroxidase as the secondary antibody were both purchased from British biotech company Abcam.

2.4. Pathological diagnoses

All the 42 patients with SPNs were pathological diagnosed postoperatively. 12 cases were benign nodules(4/12 were tuberculoma, 6/12 were inflammatory pseudotumor, 2/12 were hamartoma) and 30 cases were malignant nodules(17/30 were adenocarcinoma, 13/30 were squamous carcinoma).

2.5. Statistical methods

All data were analyzed by SPSS 19.0. Because the measured data manifested as skewed distribution, geometrical mean G(logG±s)was calculated in each group after logarithmic transformation had been carried out on each datum. Then, Student's t test was performed on both sides. Differences were considered statistically significant at P<0.05.

3. Result

The S-HGF data measured of healthy control group, benign SPNs group and malignant SPNs group is shown in Table 1Table 1 are the measured S-HGF data of healthy control group, benign SPNs group and malignant SPNs group. All the data manifest as skewed distribution(All P<0.05). Geometrical mean G(logG±s)was calculated in each group after logarithmic transformation had been carried out on each datum(Table 2).

TABLE 1 The S-HGF level(pg/ml) of healthy control group, benign SPNs group and malignant SPNs group.

Groups

Number of cases

S-HGF(x±s)

Median

 

6

       

Healthy control group

10

185.00±75.02

180(100~300)

 

Benign SPNs group

12

197.50±101.19

165(100~400)

 

Malignant SPNs group

30

467.67±424.25

395(100~1550)

 
           

TABLE 2 The comparison of S-HGF level of each group after logarithmic transformation had been carried out on each datum.

Groups

Number of cases

S-HGF( pg/ml)

G( logG±s)

95% CI

Healthy control group

10

185.00(2.24±0.17)

131.33~238.67

Benign SPNs group

12

197.50(2.25±0.20)a

133.21~261.79

Malignant SPNs group

30

467.67(2.48±0.43)b, c

309.25~626.09

       

aBenign SPNs group vs healthy control group, P>0.05

bMalignant SPNs group vs healthy control group, P<0.05

cMalignant SPNs group vs benign SPNs group, P<0.05

The S-HGF level of benign SPNs group compared with the healthy control group, there were no significant differences (P>0.05). The S-HGF levels of malignant SPNs group were significantly higher than those of healthy control group(P<0.05) and benign SPNs group(P<0.05). Furthermore, we compared the S-HGF levels of adenocarcinoma and squamous carcinoma, there were no significant differences (P>0.05, Table 3).

TABLE 3 The comparison of S-HGF level of adenocarcinoma and squamous carcinoma

Pathological types

Number of cases

S-HGF[pg/ml, G(logG±s)]

Adenocarcinoma

17

415.29(2.43±0.43)

Squamous carcinoma

13

536.15(2.54±0.45)a

aSquamous carcinoma vs adenocarcinoma, P>0.05

4. Discussion

Hepatocyte growth factor/scatter factor (HGF/SF) from the serum of hepatectomized rats was first partially purified and described by Nakamura in 1984[15]. HGF receptor encoded by the c-met proto-oncogene is a member of the tyrosine kinase class of cell surface receptors. As a kind of cytokine, the hepatocyte growth factor(HGF) has widely biological activities, including regeneration, antifibrosis, cytoprotection, and differentiation[16]. Moreover, HGF is a predominant fibroblast-derived factor that stimulates mitogenesis, motogenesis, and the invasion and metastasis of human carcinoma cells [17]. The growth and metastasis of tumors depend on angiogenesis which is the result of the imbalance of promoters and inhibitors.[张英彪9]

The S-HGF levels in patients with acute hepatitis, chronic hepatitis and cirrhosis were found to be slightly higher than those in normal subjects[18]. So the patients with various liver and gall diseases were first excluded. So far, some studies showed the S-HGF levels were significantly increased in patients with Inflammation, infection, underwent surgery or trauma. Therefore, the patients with inflammation or infection within a month and the patients underwent surgery or trauma within 6 months were both excluded. Johanna et al. [19] had concluded that patients with chronic renal failure (CRF) have a systemic HGF profile reflecting a chronic inflammatory condition with high concentration, but low biological activity, of HGF. Therefore, the patient samples with CRF were also excluded. The S-HGF levels in patients with arteriosclerosis, rheumatoid arthritis, osteoarthritis, and diabetes mellitus were reported to be significantly higher than that in healthy population. So, the patients with these diseases were excluded as well.[张英彪10]

Tsao et al.[20] showed the HGF messenger RNA(mRNA) and protein were predominantly expressed by the tumor cells in a high percentage of primary NSCLC. Our study showed serum of the healthy control group contained trace amounts of S-HGF, the S-HGF levels of the patients with benign SPNs were nearly close to the healthy control group(P<0.05) and the S-HGF levels of the patients with malignant SPNs were significantly higher than the healthy control group(P>0.05) and the benign SPNs group(P>0.05). It illustrated that the high level of S-HGF was associated with lung cancer. And it was further confirmed that S-HGF could be expressed by the carcinoma cells in NSCLC.

The S-HGF levels of part of patients with squamous carcinoma in the malignant SPNs group were observed to be higher(>700pg/ml) and the S-HGF statistical analysis by the statistical difference between the squamous carcinoma group and adenocarcinoma group, for the S-HGF, the median level of the squamous carcinoma group was 370(100-1500)pg/ml while the adenocarcinoma group was 420(100-1550)pg/ml, no statistically significant difference between the two groups(P>0.05). No further conclusions could be made, in case of the number limitation of the samples. The result confirmation should be amortized awaits further research.[张英彪11]

Further analysis of the 20 patients with high levels of S-HGF(≥250pg/ml), there are 3 patients(15%) with benign SPNs and 17 patients(85%) with malignant SPNs. Furthermore, for the 20 patients, the result shows that 1 patients (6.25%) with benign SPNs and 15 patients (93.75%) with malignant SPNs in the 16 patients with high levels of S-HGF(≥400pg/ml), It reveals that an elevated S-HGF level ≥250pg/ml in patients with SPNs are more likely to be malignant and when the S-HGF level ≥400pg/ml, malignant SPNs are highly suspected.

In conclusion, our study shows significant in the differential diagnosis between malignant and benign solitary pulmonary nodules (SPNs) for the S-FGF assay. The S-HGF levels of malignant SPNs group are significantly higher than the healthy control group(P<0.05) and benign SPNs group(P<0.05). The differences between benign SPNs group and healthy control group have no statistically significant(P>0.05). An elevated S-HGF level ≥250pg/ml in patients with SPNs are more likely to be malignant, surgical therapy should be considered. If S-HGF level ≥400pg/ml, malignant SPNs are highly suspected, surgical intervention is recommended without delay.[张英彪12]Hepatocyte growth factor/scatter factor (HGF/SF) from the serum of hepatectomized rats was partially purified and described by Nakamura for the first time in 1984. HGF receptor encoded by the c-met proto-oncogene is a member of the tyrosine kinase class of cell surface receptors. As a kind of cytokine, the hepatocyte growth factor(HGF) has widely biological activities, including regeneration, antifibrosis, cytoprotection, and differentiation[5]. Moreover, HGF is a predominant fibroblast-derived factor that stimulates mitogenesis, motogenesis, and the invasion and metastasis of human carcinoma cells[6]. The growth and metastasis of tumors depend on angiogenesis which is the result of the imbalance of promoters and inhibitors. Sengupta et al[7] had demonstrated that HGF/SF could induce angiogenesis independently of VEGF, possibly through the direct activation of the Akt and ERKs.

The S-HGF levels in patients with acute hepatitis, chronic hepatitis and cirrhosis were found to be slightly higher than those in normal subjects[8]. So the patients with various liver and gall diseases were first excluded. So far, some studies have found the S-HGF levels were significantly increased in patients with Inflammation or infection, or underwent surgery or trauma. Therefore, the patients with inflammation or infection within a month and the patients underwent surgery or trauma within 6 months were both excluded. Johanna et al[9] had concluded that patients with CRF have a systemic HGF profile reflecting a chronic inflammatory condition with high concentration, but low biological activity, of HGF. Therefore, the patients with CRF were also excluded. The S-HGF levels in patients with arteriosclerosis, rheumatoid arthritis, osteoarthritis, and diabetes mellitus were reported to be significantly higher than that in healthy population. So, the patients with these diseases were all excluded.

Tsao et al[10] had showed that HGF messenger RNA(mRNA) and protein were predominantly expressed by the tumor cells in a high percentage of primary NSCLC. It indicated in our research that the serum of the healthy control group only contained trace amounts of S-HGF, the levels of S-HGF of the patients with benign SPNs were close to those of the healthy control group(P<0.05) and the levels of S-HGF of the patients with malignant SPNs were significantly higher than those of the healthy control group(P>0.05) and the benign SPNs group(P>0.05). It illustrated the fact that high level of S-HGF was associated with lung cancer. And, it was further confirmed that S-HGF could be expressed by the carcinoma cells in NSCLC. In addition, Nagio et al[11] had proved that the levels of S-HGF of patients with SCLC were significantly higher than those of patients with benign SPNs and healthy subjects.

The levels of S-HGF of a portion of patients with squamous carcinoma in the malignant SPNs group were observed to be higher(>700pg/ml) and statistical analysis was conducted to fond the statistical difference of S-HGF between the squamous carcinoma group and the adenocarcinoma group. The S-HGF median of the squamous carcinoma group was 370(100-1500)pg/ml and the adenocarcinoma group was 420(100-1550)pg/ml, no statistically significant difference was found between the two groups(P>0.05). No firm conclusions could be made, possibly due to the limited number of cases. It is of concern and remains to be further studied.

Further analysis was taken in 20 patients with high levels of S-HGF(≥250pg/ml), 3 patients(15%) had benign SPNs and 17 patients(85%) had malignant SPNs. Further observation was made, among the 20 patients, there were 16 patients with high levels of S-HGF(≥400pg/ml), 1 patients(6.25%) had benign SPNs and 15 patients(93.75%) had malignant SPNs. It reveals that an elevated S-HGF level ≥250pg/ml in patients with SPNs are more likely to be malignant and if S-HGF level ≥400pg/ml, malignant SPNs are highly suspected.

Ujiie et al[11] had proved that the levels of HGF in serum could be useful prognostic indicators of the survival of patients with stage III NSCLC undergoing surgery and chemotherapy. Kasahara et al[12] had shown that higher HGF levels were significantly associated with a shorter progression-free survival (PFS) and overall survival (OS) in patients with non-small cell lung adenocarcinoma. The expression level of S-HGF could be a sensitive indicator and an independent judgement standard for evaluating the therapeutic effects and the prognosis in patients with lung cancer. Furthermore, understanding the role of HGF in the tumor progression may help in designing new therapeutic strategies for lung cancer.

In conclusion, the assay for S-HGF may be of some significance in the differential diagnosis between malignant and benign solitary pulmonary nodules(SPNs). The S-HGF levels of malignant SPNs group were significantly higher than those of healthy control group(P<0.05) and benign SPNs group(P<0.05). The differences between benign SPNs group and healthy control group had no statistically significant(P>0.05). An elevated S-HGF level ≥250pg/ml in patients with SPNs are more likely to be malignant, surgical therapy should be suggested. If S-HGF level ≥400pg/ml, malignant SPNs are highly suspected, active surgical intervention should be taken.

Reference

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16.Kaido, T. and M. Imamura, Hepatocyte growth factor: clinical implications in hepatobiliary pancreatic surgery. J Hepatobiliary Pancreat Surg, 2001. 8(1): p. 65-75.

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18.Tsubouchi, H., et al., Levels of the human hepatocyte growth factor in serum of patients with various liver diseases determined by an enzyme-linked immunosorbent assay. Hepatology, 1991. 13(1): p. 1-5.

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[2]Klein J S, Zarka M A. Transthoracic needle biopsy: an overview[J]. Journal of thoracic imaging, 1997, 12(4): 232-249.

[3]Wahidi M M, Govert J A, Goudar R K, et al. Evidence for the treatment of patients with pulmonary nodules: when is it lung cancer? ACCP evidence-based clinical practice guidelines[J]. CHEST Journal, 2007, 132(3_suppl): 94S-107S.

[4]Schwarz C, Schönfeld N, Bittner R C, et al. Value of flexible bronchoscopy in the pre-operative work-up of solitary pulmonary nodules[J]. European Respiratory Journal, 2013, 41(1): 177-182.

[5]Kaido T, Imamura M. Hepatocyte growth factor: clinical implications in hepatobiliary pancreatic surgery[J]. Journal of hepato-biliary-pancreatic surgery, 2001, 8(1): 65-75.

[6]Nakamura T, Matsumoto K, Kiritoshi A, et al. Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: in vitro analysis of tumor-stromal interactions[J]. Cancer research, 1997, 57(15): 3305-3313.

[7]Sengupta S, Gherardi E, Sellers L A, et al. Hepatocyte growth factor/scatter factor can induce angiogenesis independently of vascular endothelial growth factor[J]. Arteriosclerosis, thrombosis, and vascular biology, 2003, 23(1): 69-75.

[8]Tsubouchi H, Niitani Y, Hirono S, et al. Levels of the human hepatocyte growth factor in serum of patients with various liver diseases determined by an enzyme‐linked immunosorbent assay[J]. Hepatology, 1991, 13(1): 1-5.

[9]Lönn J, Shahzad F, Uhlin F, et al. High concentration but low biological activity of hepatocyte growth factor in patients with chronic renal failure[J]. Advances in Bioscience & Biotechnology, 2012, 3(4).

[10]Tsao M S, Yang Y E, Marcus A, et al. Hepatocyte growth factor is predominantly expressed by the carcinoma cells in non–small-cell lung cancer[J]. Human pathology, 2001, 32(1): 57-65.

[11]Takigawa N, Segawa Y, Maeda Y, et al. Serum hepatocyte growth factor/scatter factor levels in small cell lung cancer patients[J]. Lung Cancer, 1997, 17(2): 211-218.

[12]Ujiie H, Tomida M, Akiyama H, et al. Serum hepatocyte growth factor and interleukin-6 are effective prognostic markers for non-small cell lung cancer[J]. Anticancer research, 2012, 32(8): 3251-3258.

[13]Kasahara K, Arao T, Sakai K, et al. Impact of serum hepatocyte growth factor on treatment response to epidermal growth factor receptor tyrosine kinase inhibitors in patients with non–small cell lung adenocarcinoma[J]. Clinical Cancer Research, 2010, 16(18): 4616-4624.


[F1]可以具体一下是什么样的价值

[F2]有可能是版本的é-®é¢˜ï¼Œæ³¨æ„ä¸€ä¸‹ç©ºæ ¼

[F3]这句话需要润色一下

[F4]不是ELISAå-?

[F5]å­-体格式和其ä»-的不一样,需要注意一下

[张英彪6]Description of SPNs, which we should highlight

[张英彪7]Comparation of Several Methods in screening the lung cancer and SPNs, then highlight that why we choose the topic

[张英彪8]Description of S-HGF, and in which purpose we use S-HGF, Then propose our hypothesis about our research

[张英彪9]Discuss the HGF

[张英彪10]Disscuss samples

[张英彪11]Result analysis

[张英彪12]significance

[张英彪13]Recent reference


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