KIT receptor activation by autocrine and paracrine stem cell factor stimulates growth of merkel cell carcinoma in vitro

Krasagakis, Konstantin; Fragiadaki, Irene; Metaxari, Maria; Krüger‐Krasagakis, Sabine; Tzanakakis, George N.; Stathopoulos, Efstathios N.; Eberle, Jürgen; Tavernarakis, Nektarios; Tosca, Androniki

doi:10.1002/jcp.22431

Cited by 27 publications

(23 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, KIT in colon cancer appears to have a functionally-important growth-promoting role through KITLG, either in an autocrine and/or paracrine manner as shown by our single cell gene expression analysis, and in agreement with previous in vitro studies in colon and other cancers 18,31,32 . This is surprising because KIT signaling currently has no known functional role in normal colonocytes 33 .…”

Section: Discussionsupporting

confidence: 92%

KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers

et al. 2015

View full text Add to dashboard Cite

Background & Aims Receptor tyrosine kinase (RTK) inhibitors have advanced colon cancer treatment. We investigated the role of the RTK KIT in development of human colon cancer. Methods An array of 137 patient-derived colon tumors and their associated xenografts were analyzed by immunohistochemistry to measure levels of KIT and its ligand KITLG. KIT and/or KITLG was stably knocked down by expression of small hairpin RNAs from lentiviral vectors in DLD1, HT29, LS174T, and COLO320 colon cancer cell lines, and in UM-COLON#8 and POP77 xenografts; cells transduced with only vector were used as controls. Cells were analyzed by real-time quantitative reverse transcription PCR, single-cell gene expression analysis, flow cytometry, and immunohistochemical, immunoblot, and functional assays. Xenograft tumors were grown from control and KIT-knockdown DLD1 and UM-COLON#8 cells in immunocompromised mice and compared. Some mice were given the RTK inhibitor imatinib following injection of cancer cells; tumor growth was measured based on bioluminescence. We assessed tumorigenicity using limiting dilution analysis. Results KIT and KITLG were expressed heterogeneously by a subset of human colon tumors. Knockdown of KIT decreased proliferation of colon cancer cell lines and growth of xenograft tumors in mice, compared with control cells. KIT knockdown cells had increased expression of enterocyte markers, decreased expression of cycling genes, and, unexpectedly, increased expression of LGR5-associated genes. No activating mutations in KIT were detected in DLD1, POP77, or UM-COLON#8 cell lines. However, KITLG-knockdown DLD1 cells formed smaller xenograft tumors than control cells. Gene expression analysis of single CD44+ cells indicated that KIT may promote growth via KITLG autocrine and/or paracrine signaling. Imatinib inhibited growth of KIT+ colon cancer organoids in culture and growth of xenograft tumors in mice. Cancer cells with endogenous KIT expression were more tumorigenic in mice. Conclusions KIT and KITLG are expressed by a subset of human colon tumors. KIT signaling promotes growth of colon cancer cells and organoids in culture and xenograft tumors in mice via its ligand, KITLG, in an autocrine or paracrine manner. Patients with KIT-expressing colon tumors may benefit from KIT RTK inhibitors.

show abstract

Section: Discussionsupporting

confidence: 92%

KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Although recent studies indicated that systemic infusion of BMSC-conditioned medium improved survival in a small-animal (rat) model of FHF,16 30 certain components may be potentially harmful 31 32. Searching for key therapeutic molecules that may be useful for developing a balanced cocktail, instead of whole cells, is emerging as an exciting concept in regenerative medicine.…”

Section: Discussionmentioning

confidence: 99%

Quantitative evaluation of human bone mesenchymal stem cells rescuing fulminant hepatic failure in pigs

Shi

Zhang

Zhou

et al. 2016

Gut

View full text Add to dashboard Cite

show abstract

“…SCF is a multifunctional factor. The membrane-bound form of SCF promotes the cell proliferation and is important in tumor growth and angiogenesis (Krasagakis et al 2011). Hypoxia can increase the expression of SCF in breast cancer cells and astrocytes (Xu et al 2007;Han et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Promotes Osteogenesis of Human Placental-Derived Mesenchymal Stem Cells

Shi

et al. 2016

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Placental-derived mesenchymal stem cells (pMSCs) are promising candidates for regenerative medicine because they possess high proliferative capacity and multi-differentiation potential. Human pMSCs are residing in an environment with low oxygen tension in the body. Heme oxygenase-1 (HO-1) is known to participate in the regulation of MSC differentiation. The present study aimed to investigate the impact of hypoxia on the osteogenic differentiation of human pMSCs, and to elucidate the role of HO-1 in the osteogenic differentiation of hypoxic pMSCs. Human pMSCs were cultured under normoxia (21% O 2 ) or hypoxia (5% O 2 ) for 3 days. We found that hypoxia maintained the morphology and immunophenotype of human pMSCs. The expression of stemness markers Oct4, Nanog, and Sox2 was increased under hypoxia. After a 5-day hypoxic culture, the proliferation ability of pMSCs was increased, which might be correlated with the increased expression of stem cell factor. During osteogenic induction, hypoxia increased the expression of osteogenic genes including osteopontin, osteocalcin, and alkaline phosphatase (ALP). Moreover, hypoxia increased the mineralization and ALP levels of human pMSCs as evidenced by Alizarin Red staining and ALP staining. Upregulation of HO-1 by cobalt-protoporphyrin treatment increased the osteogenic differentiation of pMSCs under hypoxia, while inhibition of HO-1 by Zn-protoporphyrin reduced the osteogenic differentiation of hypoxic pMSCs. Taken together, our data suggest that hypoxia can promote the osteogenic differentiation of human pMSCs. Upregulation of HO-1 can further increase the osteogenesis of human pMSCs under hypoxia. Our findings will highlight the therapeutic potential of MSCs in the tissue engineering of bones.

show abstract

KIT receptor activation by autocrine and paracrine stem cell factor stimulates growth of merkel cell carcinoma in vitro

Cited by 27 publications

References 53 publications

KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers

KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers

Quantitative evaluation of human bone mesenchymal stem cells rescuing fulminant hepatic failure in pigs

Hypoxia Promotes Osteogenesis of Human Placental-Derived Mesenchymal Stem Cells

Contact Info

Product

Resources

About