Recent advances in histogenesis research of lung neuroendocrine cancers: Evidence obtained from functional analyses of primitive neural/neuroendocrine cell‐specific transcription factors

Abstract

Small cell carcinoma (SmCC) and large cell neuroendocrine carcinoma (LENEC) are categorized as neuroendocrine cancers (NECs) of the lung and have extremely poor prognoses. The lack of an effective therapeutic strategy against SmCC and LCNEC is a serious issue. Because the regulation of the cellular phenotype is complicated by the actions of various transcription factors, investigations into the function of neural/neuroendocrine cell-specific transcription factors are important for elucidating the cellular characteristics and histogenesis of SmCC and LCNEC and for establishing innovative therapeutic strategies against them. In this review, the functions of ASCL1, NeuroD1, REST, TTF1, and class III/IV POU, that are specifically and highly expressed in lung NECs, are introduced. These transcription factors transactivate and/or transrepress various genes and are involved in neural progenitor phenotyping, neuroendocrine and stem cell marker expression, and epithelial-to-mesenchymal transition. Based on the evidence that certain carcinoids express ASCL1, NeuroD1, TTF1, and class III/IV POU and that lung NECs can develop from non-NE cells/non-NEC cells, the relationships among lung NECs, carcinoid tumors, and non-NECs are discussed. Finally, a model of the histogenesis of lung NECs in view of similarities in the expression of primitive neural/neuroendocrine cell-specific transcription factors is proposed.

Expression of developing neural transcription factors in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)

“…All three cases studied here met these criteria, thus enabling a more objective and reproducible diagnosis. DNTFs are frequently expressed in HGNETs of the lung [7,16,17,19,20], and it has been suggested that they may play a major role in the histogenesis of lung neuroendocrine tumors [7]. Very little research has focused on DNTFs-with the exception of TTF1-in lung carcinoid tumors; the findings reported with TTF1 have been controversial, with positive results ranging from 0 to 69 % [10,20,21].…”

“…In tumoral pathology, DNTFs are often expressed in HGNETs of the lung [7,16,19,20] but-with the exception of TTF1-have been less extensively investigated in lung carcinoid tumors [16,20,21]. In lung carcinoids, a subgroup of DNTF-positive tumors with distinctive clinicopathologic features (peripheral location and female predominance) similar to those of DIPNECH has recently been recognized [16].…”

“…Some DNTFSs-including Achaete-scute homolog like 1 (ASCL1), thyroid transcription factor 1 (TTF1), and POU transcription factors class III/IV (POU-III/IV)-are also involved in neuroendocrine differentiation [7]. ASCL1 acts as a dual transcription factor by activating neuroendocrine markers (synaptophysin), stem cell markers (CD133, ALDH1A1), and miR-375-which functions as a sufficient inducer of neuroendocrine differentiation-and by repressing the expression of class II transactivator (CIITA) of the major histocompatibility complex, the putative tumor suppressors Dikkopf WNT signaling pathway inhibitor 1 (DKK1) and Ecadherin genes [7][8][9][10][11]. TTF1 plays a crucial role in the morphogenesis of the thyroid gland, lung, and brain [12] by activating the synthesis of thyroglobulin, thyroperoxidase, thyrotropin receptor, and surfactant proteins and by repressing myosin binding protein H and the transforming growth factor-β, which inhibit cell migration and epithelial-tomesenchymal transition, respectively [13,14].…”

“…It is directly induced by POU3F2, FOXA1, FOXA2, POU3F4, and POU4F2 [7,15]. In the lung, it is frequently expressed by lung adenocarcinomas with terminal respiratory unit differentiation and by neuroendocrine tumors [7,16,17]. POU transcription factors play essential roles in organ development and cellular differentiation.…”

“…TTF1 plays a crucial role in the morphogenesis of the thyroid gland, lung, and brain [12] by activating the synthesis of thyroglobulin, thyroperoxidase, thyrotropin receptor, and surfactant proteins and by repressing myosin binding protein H and the transforming growth factor-β, which inhibit cell migration and epithelial-tomesenchymal transition, respectively [13,14]. It is directly induced by POU3F2, FOXA1, FOXA2, POU3F4, and POU4F2 [7,15]. In the lung, it is frequently expressed by lung adenocarcinomas with terminal respiratory unit differentiation and by neuroendocrine tumors [7,16,17].…”