Activating Invasion and Metastasis in Small Cell Lung Cancer: Role of the Tumour Immune Microenvironment and Mechanisms of Vasculogenesis, Epithelial-Mesenchymal Transition, Cell Migration, and Organ Tropism

Abstract

Background

Small cell lung cancer (SCLC) harbours the most aggressive phenotype of all lung cancers to correlate with its bleak prognosis. The aggression of SCLC is partially attributable to its strong metastatic tendencies. The biological processes facilitating the metastasis in SCLC are still poorly understood and garnering a deeper understanding of these processes may enable the exploration of additional targets against this cancer hallmark in the treatment of SCLC.

Recent Findings

This narrative review will discuss the proposed molecular mechanisms by which the cancer hallmark of activating invasion and metastasis is featured in SCLC through important steps of the metastatic pathway, and address the various molecular targets that may be considered for therapeutic intervention. The tumour immune microenvironment plays an important role in facilitating immunotherapy resistance, whilst the poor infiltration of natural killer cells in particular fosters a pro-metastatic environment in SCLC. SCLC vasculogenesis is achieved through VEGF expression and vascular mimicry, and epithelial-mesenchymal transition is facilitated by the expression of the transcriptional repressors of E-cadherin, the suppression of the Notch signalling pathway and tumour heterogeneity. Nuclear factor I/B, selectin and B1 integrin hold important roles in SCLC migration, whilst various molecular markers are expressed by SCLC to assist organ-specific homing during metastasis. The review will also discuss a recent article observing miR-1 mRNA upregulation as a potential therapeutic option in targeting the metastatic activity of SCLC.

Conclusion

Treatment of SCLC remains a clinical challenge due to its recalcitrant and aggressive nature. Amongst the many hallmarks used by SCLC to enable its aggressive behaviour, that of its ability to invade surrounding tissue and metastasise is particularly notable and understanding the molecular mechanisms in SCLC metastasis can identify therapeutic targets to attenuate SCLC aggression and improve mortality.