Significance of circulating tumor cells in lung cancer: a narrative review

In cancer patients, circulating tumor cells (CTCs) are employed as "Liquid Biopsy" for tumor detection, prognosis and assessment of the response to therapy. CTCs are responsible for tumor dissemination but the mechanisms involved in intravasation, survival in the circulation and extravasation at secondary sites to establish metastases are not fully characterized. In lung cancer patients, CTCs are present in very high numbers in small cell lung cancer (SCLC) that is found disseminated in most patients upon first presentation and has a dismal prognosis. This review aims at the discussion of recent work on metastatic SCLC and novel insights into the process of dissemination derived from the access to a panel of unique SCLC CTC lines.

PubMed and Euro PMC were searched from January 1^st, 2015 to September 23^th, 2022 using the following key words: "SCLC", "NSCLC", "CTC" and "Angiogenesis" and supplemented by data from our own work.

Experimental and clinical data indicate that the intravasation of single, apoptotic or clustered CTCs occur via leaky neoangiogenetic vessels in the tumor core and not via crossing of the adjacent tumor stroma after EMT. Furthermore, in lung cancer only EpCAM-positive CTCs have been found to have prognostic impact. All our established SCLC CTC lines form spontaneously EpCAM-positive large and chemoresistant spheroids (tumorospheres) that may become trapped in microvessels in vivo and are suggested to extravasate by physical force. The rate-limiting step of the shedding of CTCs is most likely the presence of irregular and leaky tumor vessels or in case of SCLC, also via vessels formed by vasculogenic mimicry. Therefore, lower microvessel densities (MVD) in NSCLC can explain the relative rarity of CTCs in NSCLC versus SCLC.

The detection of CTCs lacks standardized techniques, is difficult in non-metastatic patients and important cell biological mechanisms of dissemination need still to be resolved, especially in respect to the actual metastasis-inducing cells. Expression of VEGF and the MVD are key prognostic indicators for tumors and ultimately, enumeration of CTCs seems to reflect neoangiogenetic vascular supply of tumors and prognosis.