Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

Abstract

Small cell lung carcinoma (SCLC) is a fast-growing, highly metastatic form of lung cancer. A major difference between SCLC and other forms of lung cancer is that SCLC tumors often respond well to chemotherapy initially; unfortunately, resistant tumors rapidly recur. In addition, despite a large number of clinical trials with a variety of therapeutic agents, little progress has been achieved in the past three decades in improving the survival of SCLC patients. These clinical observations indicate that SCLC tumors have a high degree of plasticity and rapid adaptability to changes in growth conditions. Here we consider recent evidence pointing to several levels of heterogeneity in SCLC that may explain the ability of these tumors to adjust to different microenvironment and therapeutics. In particular, we review new data pointing to the existence of several subpopulations of tumor cells that interact with each other to promote tumor growth. We also discuss how SCLC tumors that look similar at the histopathological level may actually represent distinct subtypes of tumors and how these differences impact the response to specific therapeutic agents. A better understanding of genetic and cellular heterogeneity will guide the development of personalized approaches to help SCLC patients.

Keywords: Heterogeneity; knockout mice; neuroendocrine cells; notch, small cell lung cancer (SCLC).

Figure 1

Modeling and studying SCLC in mice. (A) Deletion of Rb and p53 in the lung epithelium of mice following Cre-mediated recombination of conditional alleles results in the development of SCLC. Alterations in other cancer genes (X) can be used to generate new models and functionally study the role these genes may play in SCLC development. Individual tumors from these GEMMs can be transplanted as allografts for additional studies; (B) human SCLC cells can be obtained from tumor biopsies (from the lungs or other organs) to generate PDX in immunocompromised recipients. CTCs can be used to generate CDX models. SCLC, small cell lung cancer; GEMM, genetically engineered mouse model; PDX, patient-derived xenograft models; CTC, circulating tumor cell; CDX, CTC-derived explant.

Figure 2

Intra-tumoral heterogeneity in SCLC. The most aggressive cells in SCLC (“Cancer stem cells”) are neuroendocrine cells; these cells can give rise to non-neuroendocrine cancer cells with vascular and mesenchymal features, as well as via activation of Notch signaling. Genetic events such as amplification of the Nfib locus, contribute to metastasis in mouse models. Note that although the different subpopulations are presented as distinct entities for illustration purposes, there is certainly some overlap between at least some of these different cell types. See text for details. SCLC, small cell lung cancer.