High co-expression of IL-34 and M-CSF correlates with tumor progression and poor survival in lung cancers

Abstract

Despite recent advances in diagnosis and treatment of lung cancers, the 5-year survival rate remains unsatisfactory, which necessitates the identification of novel factors that associates with disease progression and malignant degree for improving diagnostic and therapeutic strategies. Recent progress in cancer immunology research has unveiled critical roles for colony stimulating factor 1 receptor (CSF1R) in multiple aspects of the tumor microenvironment. CSF1R is expressed on tumor-associated macrophages (TAMs), and mediates important pro-tumorigenic functions. CSF1R also provides critical autocrine signals that promote cancer cell survival and proliferation. Activation of CSF1R can be achieved by two independent ligands; macrophage colony-stimulating factor (M-CSF) and interleukin 34 (IL-34). Accordingly, the expression of these ligands in cancer is expected to result in poor prognosis. In this study, we show that IL-34 and M-CSF expression correlates with poor survival in a cohort of lung cancer patients. Importantly, high co-expression of IL-34 and M-CSF associates with the poorest survival compared to cancers that show weak or absent expression of the two ligands. Furthermore, high expression of IL-34 and M-CSF associates with advanced stages of lung cancers. Together, these results indicate a correlation between IL-34/M-CSF expression with poor survival and disease progression in lung cancer patients.

Figure 1

Correlation between IL-34 and M-CSF expression with poor survival in lung cancer patients. (A) and (b), Immunohistochemistry staining of IL-34 (a) or M-CSF (b) in primary lung cancer tissues from patients diagnosed with adenocarcinoma (ADC), squamous cell carcinoma (SCC) or small cell lung cancers (SCLC) compared to normal lung tissues. (c) Kaplan-Meier analysis showing overall survival in lung cancer patients according to M-CSF expression.

Figure 2

Correlation between M-CSF/IL-34 expression with poor survival in lung cancer patients. (a) Kaplan-Meier analysis showing overall survival in lung cancer patients that show M-CSF^Weak/Absent/IL-34^Weak/absent expression compared to M-CSF^Weak/Absent/IL-34^High group. (b) Kaplan-Meier analysis of overall survival in lung cancer patients that show M-CSF^Weak/Absent/IL-34^Weak/absent expression compared to M-CSF^High/IL-34^High group. (c) Kaplan-Meier analysis of overall survival in lung cancer patients that show M-CSF^Weak/Absent/IL-34^Weak/absent expression compared to M-CSF^High/IL-34^High group.

Figure 3

Correlation between CSF1R expression with poor survival in lung cancer patients. (a) Representative data of immunohistochemistry staining of CSF1R in primary lung cancer tissues compared to normal lung tissues. (b) Kaplan-Meier analysis showing overall survival in lung cancer patients according to CSF1R expression.

Figure 4

Correlation between CD163 expression with poor survival in lung cancer patients. (a) Representative data of immunohistochemistry staining of CD163 in primary lung cancer tissues compared to normal lung tissues. (b) High magnification images of CD163 staining in lung cancer tissues. (c) Kaplan-Meier analysis showing overall survival in lung cancer patients based on CD163 expression.

Figure 5

Correlation between M-CSF or IL-34 with CD163 expression in lung cancers. (a) Classification of lung cancer patients based on M-CSF and CD163 expression. M-CSF positive refers to samples that show high or weak expression of M-CSF. (b) Kaplan-Meier analysis showing overall survival in lung cancer patients based on M-CSF and CD163 expression. (c) Classification of lung cancer patients based on IL-34 and CD163 expression. IL-34 positive refers to samples that show high or weak expression of IL-34. (d) Kaplan-Meier analysis showing overall survival in lung cancer patients based on IL-34 and CD163 expression.

Figure 6

Association between IL-34/M-CSF expression with advanced stages in lung cancers. Bar graph analysis resembles the association between M-CSF or IL-34 expression with disease stages in lung cancer patients. Positivity rates of IL-34 (a), M-CSF (b) or both IL-34 and M-CSF (c) were calculated in each group according to disease stage.