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

Abstract

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.

Carcinocythemia: A rare entity becoming more common? A 3‐year, single institution series of seven cases and literature review

“…[22][23][24] Indeed in the literature, other myeloid-associated antigens have been described in carcinomas, including CD13 and CD14 in breast carcinoma by IHC and/or flow cytometry and CD117 in colon and lung carcinomas by IHC, so inappropriately interpreting antigen expression without other diagnostic tools is a pitfall for pathologists. [25][26][27][28] In both of our cases, however, CD45 was either equivocal (unable to be assessed compared to an isotype control) or negative, which is an extremely uncommon finding in myeloblasts (with the exception of megakaryoblasts), and would favor a nonhematolymphoid interpretation. In contrast, under expression or dim expression of CD45 is a common abnormality of neoplastic myeloblasts (3).…”

c-Kit as a Novel Potential Therapeutic Target in Colorectal Cancer

“…1,2 Although in vivo evidence is lacking for the presence of stem cells as drivers of CRC, especially in humans, many independent groups have shown that CRCs contain heterogeneous populations of epithelial cells with varying ability to self-renew and establish colonies in culture or tumors when xenotransplanted in mice. The identification of drugs that target tumor-initiating cells in CRC will provide unique, new therapeutic opportunities.…”

“…1 A number of mediators involved in the onset and termination of liver regeneration have been identified over the years, and these where categorized by the late Nelson Fausto into 3 types of interconnected pathways known as the cytokine, growth factor, and metabolic networks. 1 Given the fundamental role of the liver in systemic metabolism, it was likely that this hepatostat would reside at least in part within the metabolic network. 3 These studies revealed the tremendous proliferative ability of the hepatocyte, with an almost unlimited clonogenic potential.…”

Identification of Candidate Biomarkers Related to Diagnosis and Prognosis of Thyroid Cancer via Transcriptomic Profile Analysis

“…Receptor tyrosine kinase (KIT), a form of myeloid receptor that binds the stem cell factor, plays a major role in cancer occurrence [51]. Papers are showing that KIT is highly expressed in small cell lung cancer [52], leukemia cells [53], colon cancer [54], and neuroblastoma [55]. But KIT expression is lower in breast cancer [56] and melanoma [57].…”