The properties of tumor-initiating cells from a hepatocellular carcinoma patient's primary and recurrent tumor

Abstract

Hepatocellular carcinoma (HCC) is associated with a high morbidity and mortality due to its high rate of recurrence. However, little is known about the biological characteristics of recurrent HCC cells. A single patient's primary and recurrent HCC-derived cell lines, Hep-11 and Hep-12, respectively, were established by primary culture. These two cell lines have the same hepatitis B virus integration site and share many common amplifications and deletions, which suggest that they have the same clonal origin. While Hep-11 cells were non-tumorigenic at 16 weeks following injection of up to 10 000 cells, injection of only 100 Hep-12 cells was sufficient to initiate tumor growth, and all single Hep-12 clones were tumorigenic in immunodeficient mice. Compared with Hep-11, Hep-12 cells expressed the oval cell markers AFP, NCAM/CD56, c-kit/CD117, as well as multiple stem cell markers such as Nanog, OCT4 and SOX2. In addition, >90% of Hep-12 cells were aldehyde dehydrogenase positive. They were also less resistant to paclitaxel, but more resistant to doxorubicin, cisplatin and hydroxycamptothecin (HCPT), which had been administrated to the patient. Furthermore, Hep-12 cells expressed higher levels of poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1) than Hep-11, and PARP-1 inhibition potentiated the sensitivity to HCPT in Hep-12 cells but not in Hep-11 cells. These results indicate that a large population of the recurrent HCC-derived Hep-12 cells were tumor-initiating cells and that elevated expression of PARP-1 was related to their resistance to HCPT.

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

“…The fact that most of the recurrent HCC-originated Hep-12 cells remain as TICs even with prolonged in vitro culture has led to the identification of a TIC population expressing the a2d1 subunit 29,30 . Here we developed a protocol by combining genome-wide miRNA profiling with softagar functional screening assay based on the Hep-12 cell line, to identify miRNAs that suppress the HCC TIC fate and have successfully identified a set of miRNAs, including four most effective miRNAs (let-7c, miR-200b, miR-222 and miR-424) that suppress the stemness and tumorigenicity of a2d1 þ HCC TICs.…”

“…Future work is needed to address the driving events in the a2d1 þ cell-induced HCC, especially how the four miRNAs are deregulated in the a2d1 þ HCC TICs. 29 . The Huh7, HepG2 and SMMC7721 cell lines were originated from Japan Society for the Promotion of Science (Tokyo, Japan), American Type Culture Collection (Manassas, VA) and the Second Military Medical University of China (Shanghai, China), respectively.…”

“…On the basis of a pair of hepatocellular carcinoma (HCC) cell lines Hep-11 and Hep-12, which represent non-tumorigenic and TIC-enriched cell populations, respectively 29 , we identified a subpopulation of TICs expressing the isoform 5 of the voltagegated calcium channel a2d1 subunit (encoded by the gene CACNA2D1), which is vital for the activation of calcium signalling that controls the HCC TIC properties using an antibody, Mab1B50-1, generated against Hep-12 cells 30,31 . Here we first validate directly that a2d1 is indeed a surface marker for HCC TICs using a known a2d1 antibody and identify its prognostic role in HCC.…”

Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma

“…40 More recently, NCAM was found in cancer-initiating stem cells of the liver. 41,42 We demonstrated that in HCC, NCAM, although present in several cancer cells, was significantly down-modulated and practically absent in stroma and in vessels, thus indicating that, contrarily in other cancers, 43,44 NCAM does not stain tumor vessels of HCC.…”

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

“…Similarly, a 'CSC-TPC' phenotype with high aggressivity and tumorigenesis in animals, with markers of ESC (OCT4, SOX2 and NANOG) and with ALDH þ , ABCG2 þ , poly (ADP-ribose) polymerase þ and insulin-like growth factor-1 þ expressions displays the most competitive phenotype appearing in recurrent hepatocellular carcinoma but no special surface markers (Xu et al, 2010).…”