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

Abstract

Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer characterized by its fast growth and aggressive nature. SCLC development is strongly associated with heavy cigarette smoking. In a majority of cases, SCLC tumors have already metastasized to distant sites at the time of first diagnosis. Except in rare cases when tumors are diagnosed early, treatment options are limited and usually consist of several rounds of chemotherapy with cisplatin/ carboplatin and etoposide. While this chemotherapy regimen often results in significant response and tumor shrinkage, relapse is usually quite rapid. A number of excellent reviews have recently discussed the key clinical features of SCLC and the current lack of efficient treatment despite a large number of clinical trials in the past three decades (1-4). New therapeutic approaches, including immunotherapies, are promising but at the time this review is written, there are still no approved targeted therapies for SCLC [reviewed in (5-8)].Here we discuss emerging data in the field on the role of tumor heterogeneity in the growth of SCLC and the response of these tumors to therapy, and how mouse models have been used to identify such tumor heterogeneity and investigate its role. We use the term "intertumoral" heterogeneity to describe how SCLC tumors in patients or mice evolve differently at the genetic and epigenetic level during tumor progression and metastasis. We use the term "intratumoral" heterogeneity to describe the different subpopulations of cells within tumors at any given time; in 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.

Small Cell Lung Cancer Therapeutic Responses Through Fractal Measurements: From Radiology to Mitochondrial Biology

“…In the case of cisplatin, four cell lines were more sensitive to this treatment, and four cell lines H69, H446, SBC5, and DMS273 had an EC 50 value close to or higher than control BEAS-2B cells (Table 1). Cellular differences in response to cisplatin were comparable with clinical chemotherapy treatment, which for SCLC tumors often results in significant tumor shrinkage, however, relapse is usually quite rapid because of genetic and non-genetic tumor heterogeneity [20].…”

Tumor Heterogeneity Underlies Differential Cisplatin Sensitivity in Mouse Models of Small-Cell Lung Cancer

“…To date, the intrinsic complexity of SCLC as well as a lack of tumor material has limited our ability to develop effective treatment modalities. Analysis of available patient material, patient-derived xenografts (PDXs), circulating tumor cells-derived explants (CDXs), and genetically engineered mouse models (GEMMs) provides growing evidence for extensive intrinsic and acquired heterogeneity in SCLC ( Borromeo et al., 2016 , Calbo et al., 2011 , Drapkin et al., 2018 , Gazdar et al., 2015 , George et al., 2015 , Huang et al., 2018 , Lim et al., 2017 , Pozo et al., 2018 , Shue et al., 2018 , Zhang et al., 2018 ). This is further complicated by evidence for trans-differentiation and existence of combined SCLC-NSCLC ( Niederst et al., 2015 , Sequist et al., 2011 , Zhao et al., 2018 ).…”

Potential application of cell reprogramming techniques for cancer research

“…Genetically, some tumors, such as medulloblastomas [ 66 ], hepatocellular carcinomas [ 67 ], small cell lung carcinomas (SCLCs) [ 68 ], and pancreatic adenocarcinomas [ 69 ], are composed of such genetic subpopulations of each specific cancer [ 70 ]. Different cell subpopulations with a certain cell identity may be dominantly represented by cell reprogramming.…”

“…Single-nucleotide mutants in iPSCs are identified by high-throughput next-generation sequencing analyses. These analyses have identified an average of ten protein-coding mutations per human iPSC line [ 68 , 85 ]. Thus, further investigation is required to identify approaches aimed at preventing these mutations during the cellular reprogramming of cancer cells.…”