Growth stimulation of colorectal carcinoma cells via the c-kit receptor is inhibited by TGF-β1

Bellone, Graziella; Silvestri, S.; Artusio, Elisa; Tibaudi, D.; Turletti, Anna; Geuna, Massimo; Giachino, Claudia; Valente, Guido; Emanuelli, G; Rodeck, Ulrich

doi:10.1002/(sici)1097-4652(199707)172:1<1::aid-jcp1>3.0.co;2-s

Cited by 67 publications

(48 citation statements)

References 25 publications

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“…More recently, Sammarco et al detected KIT-positive staining in the epithelium of the neoplastic colon in 25% of patients examined (10). In a previous preliminary analysis conducted on a small number of patients, we reported KIT immunoreactivity in several malignant mucosa specimens compared to normal counterparts (38). The present evaluation of KIT expression using a polyclonal antibody recommended for accurate GIST diagnosis (39) and using a larger number of CRC cases at different disease stages as well as adenomas, confirms that KIT overexpression is rare in these tumor forms.…”

Section: Discussionmentioning

confidence: 47%

KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and outcomes

Bellone¹,

Smirne²,

Carbone³

et al. 2006

Int J Oncol

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Abstract. Autocrine/paracrine stimulation of KIT has been observed in colorectal carcinoma (CRC) cell lines. We investigated the expression of KIT and stem cell factor (SCF) in CRC in comparison with premalignant colon lesions and normal colonic mucosa to assess the prognostic and therapeutic relevance of this receptor/ligand system in CRC. Transcript levels of c-kit and the two SCF splicing variants were determined quantitatively by real-time RT-PCR using cDNA obtained from normal, premalignant and malignant snap frozen colon tissue specimens. Immunohistochemistry with specific anti-KIT and anti-SCF antibodies was performed on paraffin-embedded tissue sections in order to localize the relative protein expression in epithelial compartments. Approximately 10% of patients expressed KIT in their adenoma or primary tumor. The majority of KIT-positive carcinomas co-expressed SCF. Real-time RT-PCR showed expression of c-kit and SCF transcripts in all cDNA specimens examined. A significant association between the co-expression of KIT/SCF and a worse clinical outcome was found. In conclusion, KIT expression was observed in a proportion of premalignant and malignant colonic lesions, while it was virtually absent in normal colon mucosa. Moreover, the majority of KIT-positive carcinomas co-expressed SCF, suggesting the possibility of aberrant signaling by an autocrine loop, as confirmed by the negative prognostic value of this association. Therefore, in the subset of CRC patients with concomitant KIT/SCF expression, the activity of Imatinib mesylate, a selective inhibitor of specific tyrosine kinases including KIT, may be exploited in combination with standard therapy.

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Section: Discussionmentioning

confidence: 47%

KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and outcomes

Bellone¹,

Smirne²,

Carbone³

et al. 2006

Int J Oncol

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“…Similarly, reports offering a contrasting view on the role of c-KIT in CRC have been published: Bellone et al showed that increased immunoreactivity to c-KIT is associated with neoplastic colonic tissues [10], whereas other groups have suggested that immunohistochemical staining for c-KIT is a rare event in human CRC [11,12,13]. A possible reason for these conflicting results is that the authors did not correlate the expression of c-KIT in both the normal and neoplastic colon tissue for each patient examined.…”

Section: Discussionmentioning

confidence: 99%

“…With regard to CRC, while some authors have demonstrated the expression of both c-KIT transcript and protein [10], a number of other reports have shown rare if any expression of c-KIT in CRC tissue [11,12,13]. Most of these studies were retrospective and not specifically aimed at investigating c-KIT expression in CRC [11,12], and did not analyze both the RNA and protein levels of c-KIT in each patient.…”

Section: Introductionmentioning

confidence: 99%

Expression of the proto-oncogene c-KIT in normal and tumor tissues from colorectal carcinoma patients

Sammarco

Capurso²,

Coppola³

et al. 2004

Int J Colorectal Dis

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Background and aims: The proto-oncogene c-KIT encodes a tyrosine kinase receptor essential during embryonic development and postnatal life. Although deregulated expression of c-KIT has been reported, its role in colorectal carcinoma remains controversial: some authors have described a correlation between c-KIT expression and colorectal cancer (CRC), while others have failed to detect the receptor in the majority of neoplasia examined. To address this question, we designed a prospective study to analyze the expression of c-KIT in normal and neoplastic colonic mucosa of the same patient. Patients and methods: We analyzed the tissues of 20 patients undergoing surgical resection for colorectal carcinoma by reverse transcriptase-polymerase chain reaction, Western blot and immunohistochemistry, whose results were correlated with histopathological parameters. Results: Most patients (90%) showed c-KIT expression in normal tissue both at RNA and protein level, while in neoplastic tissue it was observed in 30% of patients at RNA level and in 10% at protein level. By immunohistochemistry the localization of c-KIT protein in the normal colon was restricted to interstitial cells scattered in the stroma, whereas the non-neoplastic epithelium was always negative. The mucinous carcinomas were all c-KIT negative, whereas the only case in which c-KIT was displayed in the neoplastic epithelium was a G3 adenocarcinoma. Conclusion: Most colorectal carcinomas do not express c-KIT. We suggest that c-KIT expression is rarely present in this neoplasia; thus, the use of receptor inhibitors should be conducted in selected sub-groups of colon carcinoma patients, subsequent to the clear demonstration of c-KIT overexpression in the neoplastic cells.

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“…Simultaneous expression of c-kit and SCF has been reported in colon, gastric, and lung cancer cell lines, in which a growth/migrationstimulating autocrine loop has been demonstrated (Bellone et al, 1997;DiPaola et al, 1997;Hassan et al, 1998). On the other hand, in melanomas and in breast and thyroid carcinomas a loss of expression of these molecules, in comparison with normal melanocytes and mammary or thyroid epithelium, has been described (Moretti et al, 1999;Natali et al, 1992Natali et al, , 1995Welker et al, 2000).…”

Section: Esposito Et Almentioning

confidence: 99%

The Stem Cell Factor–c-kit System and Mast Cells in Human Pancreatic Cancer

Espósito

Kleeff

Bischoff

et al. 2002

Laboratory Investigation

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SUMMARY:Stem cell factor (SCF) and its receptor c-kit take part in the regulation of developmental processes of mast cells, hematopoietic stem cells, and melanocytes, as well as in the growth control of human malignancies. To explore the possible role of the SCF-c-kit system and of mast cells in pancreatic cancer, the concomitant expression and distribution of the two molecules were examined in 17 normal and 26 cancerous human pancreatic tissues and in 6 cultured pancreatic cancer cell lines. Mast cell distribution was also evaluated in the same tissue samples. In addition, the effects of SCF and of the c-kit tyrosine-kinase inhibitor STI571 on the growth of the cancer cell lines and of the normal pancreatic ductal cell line TAKA-1 were assessed. SCF immunoreactivity was absent in acinar, ductal, and islet cells of the normal pancreas and faint in pancreatic cancer tissues and cell lines. In contrast, c-kit was clearly present in some normal and hyperplastic ducts of the normal pancreas, in the cancer cells of 73% of the tumor samples, and in all the cell lines tested. Mast cells, identified by tryptase and chymase immunostaining on consecutive tissue sections, showed immunoreactivity for SCF and c-kit in both normal and cancerous specimens and their number was significantly increased (p ϭ 0.03) in pancreatic cancer compared with the normal pancreas. SCF showed a dose-dependent growth inhibitory effect on TAKA-1 cells (p Ͻ 0.001), whereas pancreatic cancer cells were resistant to the SCF-induced growth inhibition. Nonetheless, the growth of TAKA-1 cells and pancreatic cancer cells was inhibited by the c-kit tyrosine kinase inhibitor STI571. In conclusion, the SCF-c-kit system, possibly with the contribution of mast cells, may have a growth-regulating role in the normal pancreas, which is altered during malignant transformation. (Lab Invest 2002, 82:1481-1492.

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Growth stimulation of colorectal carcinoma cells via the c-kit receptor is inhibited by TGF-β1

Cited by 67 publications

References 25 publications

KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and outcomes

KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and outcomes

Expression of the proto-oncogene c-KIT in normal and tumor tissues from colorectal carcinoma patients

The Stem Cell Factor–c-kit System and Mast Cells in Human Pancreatic Cancer

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