How to target small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is a highly malignant disease with dismal prognosis. Although great progress has been made in investigating genetic aberrations and putative drivers of this tumor entity, the mechanisms of rapid dissemination and acquisition of drug resistance are not clear. The majority of SCLC cases are characterized by inactivation of the tumor suppressors p53 and retinoblastoma (Rb) and, therefore, interchangeable drivers will be difficult to target successfully. Access to pure cultures of SCLC circulating tumor cells (CTCs) and study of their tumor biology has revealed a number of new potential targets. Most important, expression of chitinase-3-like-1/YKL-40 (CHI3L1) which controls expression of vascular epithelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) was newly described in these cells. The process switching CHI3L1-negative SCLC cells to CHI3L1-positive CTCs seems to be associated with cytokines released by inflammatory immune cells. Furthermore, these CTCs were found to promote monocyte-macrophage differentiation, most likely of the M2 tumor-promoting type, recently described to express PD-1 immune checkpoint antigen in SCLC. In conclusion, dissemination of SCLC seems to be linked to conversion of regular tumor cells to highly invasive CHI3L1-positive CTCs, which are protected by immune system suppression. Besides the classical targets VEGF, MMP-9 and PD-1, CHI3L1 constitutes a new possibly drugable molecule to retard down dissemination of SCLC cells, which may be similarly relevant for glioblastoma and other tumor entities.

Keywords: Inflammation; YKL-40; chitinase 3-like1 (CHI3L1); chronic obstructive pulmonary disease (COPD); circulating tumor cells (CTCs); prognostic marker; secretome; small cell lung cancer (SCLC).

Figure 1. Proposed model of SCLC CTC dissemination

SCLC is initiated by a series of mutations concerning p53 and Rb tumor suppressors as well as one of several oncogenes which function as tumor drivers. Factors released by the tumor cells attract immune effector cells causing local inflammation (IFL). Tumor-associated macrophages (TAM) secrete cytokines which promote cancer cell growth and seem to induce CHI3L1 in putative precursors of CTCs. Furthermore, TAMs express immune checkpoint proteins (light green macrophages), such as PD-1/PD-L1, which provide suppression of antitumor lymphocyte responses. The few susceptible SCLC cells (red) which acquired the ability to produce CHI3L1 and express VEGF and MMP9 enter the bloodstream, possibly after epithelial-to-mesenchymal transition (EMT). CTCs reach secondary sites for invasion and formation of metastases. Their production of CHI3L1 leads to monocyte-macrophage differentiation and these new suppressive TAMs may shield the disseminated SCLC cells against attacks of the immune system, such promoting formation of secondary tumor lesions.