Advances in the role of circulating tumor cell heterogeneity in metastatic small cell lung cancer

Abstract

Small cell lung cancer (SCLC), a highly aggressive malignancy, is rapidly at an extensive stage once diagnosed and is one of the leading causes of death from malignancy. In the past decade, the treatment of SCLC has largely remained unchanged, and chemotherapy remains the cornerstone of SCLC treatment. The therapeutic value of adding immune checkpoint inhibitors to chemotherapy for SCLC is low, and only a few SCLC patients have shown a response to immune checkpoint inhibitors. Circulating tumor cells (CTCs) are tumor cells shed from solid tumor masses into the peripheral circulation and are key to tumor metastasis. Single-cell sequencing has revealed that the genetic profiles of individual CTCs are highly heterogeneous and contribute to the poor outcome and prognosis of SCLC patients. Theoretically, phenotypic analysis of CTCs may be able to predict the diagnostic significance of new potential targets for metastatic tumors. In this paper, we will discuss in depth the heterogeneity of CTCs in SCLC and the value of CTCs for the diagnosis and prognosis of SCLC and as relevant tumor markers in metastatic SCLC.

Keywords: circulating tumor cell; heterogeneity; immunotherapy; small cell lung cancer; tumor micro‐environment.

Figure 1

The classification of lung tumors. AC, atypical carcinoid; NEN, neuroendocrine neoplasm; NET, neuroendocrine tumor; SCLC, small cell lung cancer; TC, typical carcinoid.

Figure 2

Representation of CTC‐mediated metastasis in small cell lung cancer (SCLC). CTCs that have sloughed off the primary tumor and tumor core and circulated in blood vessels either directly or via EMT. Activation of macrophages (MΦ*) enhances extracellular matrix lysis and neovascularization by matrix metalloproteinase‐9 (MMP‐9) and blood vessel endothelial growth factor (VEGF), respectively. CTCs can be single intact CTCs, apoptotic CTCs, or small clusters of cells. Extravasion of CTCs is supported by the local recruitment of macrophages, which may then release a second wave after the formation of new blood vessels. The invading cells may then generate metastases. CTC, circulating tumor cell.