Connective tissue growth factor expression in endocrine tumors is associated with high stromal expression of α-smooth muscle actin

Abstract

Objective: Complications due to fibrosis development are common in patients with well-differentiated endocrine carcinomas in the small intestine (ileal carcinoids). Connective tissue growth factor (CTGF) expression in ileal carcinoids may be related to this fibrosis development. This study aimed to examine CTGF expression in relation to local myofibroblast differentiation in a large series of ileal carcinoids and in different types of endocrine tumors. Methods: Immunoreactivity (IR) for CTGF and a-smooth muscle actin (a-SMA), a marker for myofibroblasts, was compared in serial tumor tissue sections from 42 patients with ileal carcinoids and from 80 patients with other endocrine tumors. Western blot was performed on an additional 21 patients with ileal carcinoids. Results: CTGF IR was present in O50% of tumor cells in all 42 ileal carcinoids and in 2 out of 14 endocrine pancreatic tumors, 4 out of 6 rectal carcinoids, and 1 out of 5 lung carcinoids. Tumors with abundant CTGF expression also displayed a-SMA IR in stromal fibroblast-like cells, whereas other endocrine tumors displayed less or no CTGF and a-SMA IR. Protein bands corresponding to full-length CTGF (36-42 kDa) were detected in protein lysates from ileal carcinoids. Conclusion: CTGF is uniquely prevalent in ileal carcinoids when compared with most other endocrine tumor types. Immunoreactive cells are adjacent areas with increased fibrovascular stroma that express a-SMA. This supports a potential role for CTGF in myofibroblast-mediated fibrosis associated with ileal carcinoids, and indicates that CTGF should be investigated as a target for future therapy.

Expression of connective tissue growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their clinico-pathological significance

“…Serotonin production is occasionally seen in GNETs (Tsolakis et al 2008) and its relationship to CTGF is not known in these tumours. In a recent study, a correlation was observed between CTGF and serotonin production in NETs even when ileal NETs were excluded from the analysis (Cunningham et al 2010). IGF1 expression has been reported only in ileal NETs but occasional cases were investigated (Nilsson et al 1992, Wulbrand et al 2000.…”

Input of microenvironmental regulation on colorectal cancer: Role of the CCN family

“…Although high expression of CCN2 is the hallmark of good prognosis of CRC, its roles in CRC cell differentiation and proliferation are still under investigation. In previous studies, Cunningham et al [38] showed that CCN2 expression was positively correlated with α-smooth muscle actin expression, which in turn indicated a potential role for CCN2 in myofibroblast-mediated fibrosis associated with ileal carcinoids. Moreover, Kaltsas et al [39] in 2010 demonstrated that CCN2 involved in the neoplastic transformation into ileal carcinoids is positively correlated with tumours larger than 1 cm.…”

Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum

“…Treatment with CTGF-neutralizing antibodies has already been shown to decrease tumour growth and metastasis in pancreatic cancer models (Leask & Abraham 2006). SI-NETs have a high expression of CTGF compared to other neuroendocrine tumours (Kidd et al 2007c, Cunningham et al 2010. Immunoreactivity was strongest in SI-NET cells adjacent to fibrovascular stroma, suggesting a local effect on the tumour stroma interaction at the invasion border.…”

“…In contrast to quiescent fibroblasts, CAFs are able to proliferate, produce growth factors and ECM (Kalluri 2016). Compared to other neuroendocrine tumours, SI-NETs have a high expression of αSMA in the fibroblast component of the TME both in primary tumours and metastases (Facco et al 1998, Kidd et al 2007c, Cunningham et al 2010. Further evidence on the presence of synthetic fibroblasts in SI-NETs was detected in primary cultures in which cells from the tumour stroma developed the typical stellate shape of CAFs and increased growth factor transcription after stimulation with transforming growth factor beta 1 (TGFβ1, see later) (Kidd et al 2007c).…”

“…Furthermore, CTGF co-localized with serotonin in 93% of tumour cells and with TGFβ Endocrine-Related Cancer in 80%. The tumour stroma, however, shows little CTGF immunoreactivity (Cunningham et al 2010). High expression of CTGF in tumour tissue of NETs was found to be correlated with SI-NETs, MF and serum levels of CTGF (Kidd et al 2007c).…”