Abstract
Simple SummaryThe aim of this study was to gain a better understanding of cancer stem cells, which are a small subpopulation of tumor cells with high plasticity driving tumor growth and metastasis. Here we isolated two novel colorectal cancer cell lines originating from a rectal neuroendocrine carcinoma and a colorectal adenocarcinoma, depicting stem-like properties. These in vitro models offer the possibility to evaluate pathophysiological mechanisms in order to develop tailored therapeutic strategies for distinct colorectal malignancies. Investigations revealed gene copy number gain of the N-myc proto-oncogene for both. Accordingly, inhibition of the protein–protein interaction of myc and N-myc proto-oncogenes with the myc-associated factor X utilizing small molecule KJ-Pyr-9, exhibited a significant reduction in survival of both cell lines by the induction of apoptosis. Consequently, the blockage of these interactions may serve as a possible treatment strategy for colorectal cancer cell lines with gene copy number gain of the N-myc proto-oncogene.Cancer stem cells (CSC) are crucial mediators of cancer relapse. Here, we isolated two primary human colorectal cancer cell lines derived from a rectal neuroendocrine carcinoma (BKZ-2) and a colorectal adenocarcinoma (BKZ-3), both containing subpopulations with potential stem-like properties. Protein expression of CSC-markers prominin-1 and CD44 antigen was significantly higher for BKZ-2 and BKZ-3 in comparison to well-established colon carcinoma cell lines. High sphere-formation capacity further confirmed the existence of a subpopulation with potential stem-like phenotype. Epithelial–mesenchymal transition markers as well as immune checkpoint ligands were expressed more pronounced in BKZ-2. Both cell populations demonstrated N-myc proto-oncogene (NMYC) copy number gain. Myc proto-oncogene (MYC)/NMYC activity inhibitor all-trans retinoic acid (ATRA) significantly reduced the number of tumor spheres for both and the volume of BKZ-2 spheres. In contrast, the sphere volume of ATRA-treated BKZ-3 was increased, and only BKZ-2 cell proliferation was reduced in monolayer culture. Treatment with KJ-Pyr-9, a specific inhibitor of MYC/NMYC-myc-associated factor X interaction, decreased survival by the induction of apoptosis of both. In summary, here, we present the novel colorectal cancer cell lines BKZ-2 and BKZ-3 as promising cellular in vitro models for colorectal carcinomas and identify the MYC/NMYC molecular pathway involved in CSC-induced carcinogenesis with relevant therapeutic potential.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide and second most common cause of cancer-related mortality, with 1.8 million new cases and approximately 861,000 deaths in 2018 as reported by the World Health Organization (WHO) GLOBOCON database [1]
We present the establishment of two primary human colorectal cancer cell lines that contain a subpopulation with potential stem-like properties
As initial steps to that respect, we further tested for the impact and role of all-trans retinoic acid (ATRA) and the Myc proto-oncogene (MYC)/N-myc proto-oncogene (NMYC) inhibitor KJ-Pyr-9 in these cells, as both are interfering with MYC/NMYC signaling in cancer stem cells (CCSC)
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide and second most common cause of cancer-related mortality, with 1.8 million new cases and approximately 861,000 deaths in 2018 as reported by the World Health Organization (WHO) GLOBOCON database [1]. A comparatively rare and poorly understood subtype of CRC is the neuroendocrine carcinoma (NEC), representing a subgroup of neuroendocrine neoplasms comprised of poorly-differentiated neoplasms originating from epithelial cells of the endocrine or nervous system [4]. According to the WHO classification of 2010, colorectal gastro-entero-pancreatic neuroendocrine-carcinoma (GEP-NEC) is a rare and aggressive variant of neuroendocrine tumors (NET) as well as CRC with more than one third having metastatic disease at the time of diagnosis [5,6]. Some established cellular model lines were derived from primary native tumor tissue [7,8,12], such cell lines still lack cancer stem cell characteristics. Important regulators of cancer stem cell characteristics include the members of the MYC transcription factor family, consisting of
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