Despite advances in various diagnostic technologies, screening tools to detect NSCLC at an early stage are still very limited 17. So far, conventional biomarkers such as CEA and CYFRA21-1 lack sufficient discriminatory power for reliable screening 18. Routine CT-scans have been proposed for high-risk patient groups, however, they are associated with radiation exposure to patients and cause a great financial burden on the health system 17,19. Clearly, early diagnosis is elementary to improve the outcome of NSCLC patients by providing therapy at the earliest possible cancer stage. Thus, innovative, non-invasive screening tools are urgently needed. Furthermore, preoperative biomarkers may predict prognosis and tumor response. Thereby, the best treatment approach can be tailored individually for each NSCLC patient. One such emerging biomarker is the multifunctional cytokine S-MK. Due to overexpression in diverse malignant tumors including NSCLC, it has recently been implicated in the role of tumor biology 6. Moreover, various reports have suggested a correlation of S-MK expression levels and worse prognosis as well as chemotherapy resistance 11,20−22.
In this study the value of S-MK both as a diagnostic and as a prognostic marker of NSCLC was assessed retrospectively. This was done by analyzing preoperative S-MK concentration in NSCLS patients. A normal reference range of S-MK expression in healthy individuals has not been established, yet 6. This is mainly due to the lack of large-scale population studies. For this reason, blood donors served as healthy control in this trial. In line with previous reports 11,18,21 we found S-MK to be significantly overexpressed in NSCLC patients with a more than threefold median value compared to healthy controls. There was no difference between squamous cell cancer and adenocarcinoma, suggesting a potential functional role of MK in NSCLC regardless of its histological subtype.
To evaluate the clinical utility of S-MK as a screening tool a ROC analysis was carried out. Thereby, a high diagnostic power was found for S-MK to detect NSCLC. So far, a threshold for S-MK levels to differentiate healthy and cancer patients has not been established, yet. Yuan et al. determined an optimal cut-off value of 400 pg/ml to distinguish between malignant and benign pulmonary disease 11. A cut-off value of 323 pg/ml was proposed by Meng et al. to discriminate malignant from benign thyroid nodules 23. Based on our data, a threshold of 416 pg/ml S-MK provided optimal sensitivity of 92% and still reasonable specificity of 68%. The results of this study highlight the potential of MK as a clinical biomarker. They suggest that determination of serum levels may aid to diagnose NSCLC pre-surgically.
In order to assess the prognostic value of MK expression in NSCLC patients, preoperative S-MK levels were correlated with clinicopathological parameters. There was a trend of rising S-MK levels with progression of tumor stage and local recurrence. Dividing NSCLS patients into low- and high-grade expressors a statistically significant difference in overall survival and local tumor recurrence was observed. Patients with high levels of S-MK were found to suffer earlier from local recurrence. There was a similar trend for distant cancer recurrence, although not in a statistically significant manner. Moreover, the S-MK level was identified as an independent prediction factor for overall survival. Patients expressing high levels of S-MK had a shorter overall survival and a relative risk of death of 2.6 compared to low expressing patients. Altogether, this prognostic function makes S-MK valuable for personalized outcome prediction in NSCLC patients.
The results discussed above already strongly suggest a certain functional role of MK in the tumor biology of NSCLC. In line with this, previous in vitro studies have confirmed that S-MK is actively involved in tumorigenesis by promoting tumor cell growth, migration and metastasis. MK was found to prevent autophagy-mediated cell death by the Akt/ mTORC1 pathway 24,25 and exhibit angiogenic activities 26,27. Moreover, Zhang et al. were able to show that MK enhances chemoresistance by increasing anti-apoptotic protein expression 28. Furthermore, first studies have demonstrated that tumor growth can effectively be suppressed by S-MK inhibition using antibody trapping 29 30. Due to these protumorigenic effects, MK may be considered as a novel target for NSCLC treatment approaches in the future.
Further research is required to study the dynamic changes of S-MK level over the course of tumor disease in more detail. In hepatocellular carcinoma and breast cancer it has already confirmed that S-MK decreases after sufficient surgical resection and in turn rebounds in case of incipient relapse 12,13. This aspect is of great importance when looking at the use of S-MK for postoperative monitoring to predict treatment response as well as disease recurrence.
Limitations of this study are the fact that only healthy controls were compared with NSCLC patients. Benign pulmonary inflammatory nodules are an important differential diagnosis for suspected lung cancer. Therefore, sufficient distinction of NSCLC patients not only from healthy individuals but also from patients with inflammatory disease is necessary. Since MK is a multifunctional growth factor it is known to be slightly increased in inflammation, too. However, the results of previous studies by Xia et al. have already shown that patients with benign pulmonary disease exhibit only marginally elevated S-MK levels lacking a significant difference when compared to healthy controls. On the other hand, there was a significant overexpression of S-MK in NSCLC patients compared to patients with benign pulmonary disease. Thus, it can be postulated that the slight increase in benign pulmonary disease is different from the overexpression in lung cancer and can be neglected.
Although S-MK was confirmed to be significantly overexpressed In NSCLC patients, its sensitivity and specificity is not yet sufficient for it to be applied as a sole screening marker for NSCLC in clinical routine. This is partly due to the low incidence of NSCLC in the general population. Having mentioned other biomarkers such as CYFRA21 and CEA, S-MK may, however, contribute to the discriminatory power when used as an additional biomarker. Therefore, it would be worth to reassess the diagnostic value of MK using a multimarker panel in future studies.
In conclusion, this monocentric study has confirmed that MK is significantly overexpressed in patients with NSCLC and that S-MK can serve as an indicator for patient outcomes. Overall, our data weighs in favor for the minimally-invasive S-MK as an additional diagnostic and prognostic marker for NSCLC which could be of great relevance to clinical practice and therefore warrants further research.