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Neuroendocrine and epithelial markers of small cell lung cancer

Bryant, Jennifer

[Thesis]. Manchester, UK: The University of Manchester; 2015.

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Abstract

Small cell lung cancer (SCLC) is an extremely aggressive disease characterized by early metastasis and acquired resistance to therapy. SCLC is distinguished by its neuroendocrine (NE) component; the role of which is not fully understood in metastasis and response to therapy. Patients respond exceptionally well to first round chemotherapy; however, relapse with therapy-resistant tumours is virtually inevitable. Hypoxic regions within tumours can contribute towards metastasis and therapy resistance, highlighting hypoxia-targeted therapy as a novel approach for improving treatment for SCLC patients. Tumours are highly phenotypically heterogeneous, raising debate over the roles played by each cell type. Analysis of NE and epithelial markers in SCLC cell lines highlighted this inter-tumour heterogeneity. Further heterogeneity is displayed in SCLC xenograft tumours that show areas of dual epithelial and NE marker expression as well as regions negative for both markers. Irradiating xenograft tumours enhanced heterogeneity of the NE marker, pro-opiomelanocortin (POMC), which is ectopically secreted by a subset of SCLC tumours. Examining changes in marker expression post-therapy could provide vital information regarding transitions that can serve to guide therapy. SCLC is a highly metastatic disease. The role of the NE phenotype in human SCLC is not fully understood, but is considered essential for metastasis in murine models. Sub-cutaneous, intravenous and intra-splenic injection were carried out and resulted in no metastasis, spontaneous tumour generation and peripheral liver tumour growth, respectively. POMC expression was present and extremely heterogeneous within the liver, suggesting that NE properties are maintained in metastases; however, further work is necessary to develop a more consistent metastatic model that can be used to assess responses to therapy in a more clinically relevant setting. SCLC tumours proliferate rapidly and outgrow their nutrient and oxygen supplies, resulting in hypoxic conditions. Here, carbonic anhydrase IX (CA IX) becomes up-regulated in order to maintain pH levels suitable for survival. The specific CA IX inhibitor, S4, induces hypoxia-specific cell death in vitro and impairs tumour growth in vivo. This response is further accentuated by combining S4 with single or repeated cisplatin doses. Combination treatment reduced gene expression of S-phase kinase-associated protein (Skp2), associated with cisplatin resistance. CA IX inhibition combined with cisplatin chemotherapy therefore presents a novel treatment for SCLC tumours that could reduce therapy resistance. In summary, heterogeneity is extremely important when choosing treatment options for SCLC and must be considered when basing treatment on single biopsies. NE and epithelial markers are present within sub-cutaneous and liver tumours; however, a reliable multi-organ metastatic model is necessary to fully appreciate the role of these markers in the spread of SCLC. Hypoxic regions within sub-cutaneous xenograft tumours upregulate CA IX. Inhibition of this enzyme resulted in impaired tumour growth, particularly when used together with cisplatin. Combining CA IX inhibition with cisplatin presents a much-needed novel therapy for SCLC.

Layman's Abstract

Small cell lung cancer (SCLC) is the most aggressive form of lung cancer. SCLC spreads extremely rapidly and responds poorly to repeated rounds of chemotherapy. This type of lung cancer is different from the most common type, non-small cell lung cancer (NSCLC), in that it has the ability to secrete hormones into the circulation. The ability of SCLC tumours to produce hormones may also enable cells to develop characteristics that allow them to spread or resist the effects of therapy. Staining for various markers revealed that hormone-secreting cells were present in human cells when grown in mice, but to differing extents within different regions. Differences were most evident following radiation therapy and could therefore mark cells responding better or worse to therapy. These hormone-secreting cells could play an important role in the spread of tumours; therefore, substantial efforts were put into generating a model of metastatic human SCLC in mice. Injecting cells into the spleens of animals was able to induce tumour growth in the livers of mice, but there was no further spread. Hormone-secreting cells were found within the liver and could be important in the growth of tumours within this organ. A model displaying tumour growth in multiple organs would enable for a greater understanding of the importance of these cells to be achieved. Tumour cells injected under the skin of mice grew into tumours that displayed regions of low oxygen (hypoxia). Hypoxic cells are notoriously difficult to kill through conventional therapies. Within these cells, an enzyme involved in controlling acid build up is unregulated. Drugs, such as S4, are being developed that can stop this enzyme from working, causing cancerous cells to become acidic and die. S4 was able to induce cell death in SCLC cells in dishes kept in low oxygen conditions. Treating mice with S4 reduced tumour growth rates. When cisplatin was used in addition to S4, growth rate was reduced even further. S4 could therefor be used alongside cisplatin chemotherapy to enhance the effects of conventional treatment for SCLC patients.