Thymic stromal lymphopoietin (TSLP) inhibits human colon tumor growth by promoting apoptosis of tumor cells

Abstract

Thymic stromal lymphopoietin (TSLP) has recently been suggested in several epithelial cancers, either pro-tumor or anti-tumor. However, the role of TSLP in colon cancer remains unknown. We here found significantly decreased TSLP levels in tumor tissues compared with tumor-surrounding tissues of patients with colon cancer and TSLP levels negatively correlated with the clinical staging score of colon cancer. TSLPR, the receptor of TSLP, was expressed in all three colon cancer cell lines investigated and colon tumor tissues. The addition of TSLP significantly enhanced apoptosis of colon cancer cells in a TSLPR-dependent manner. Interestingly, TSLP selectively induced the apoptosis of colon cancer cells, but not normal colonic epithelial cells. Furthermore, we demonstrated that TSLP induced JNK and p38 activation and initiated apoptosis mainly through the extrinsic pathway, as caspase-8 inhibitor significantly reversed the apoptosis-promoting effect of TSLP. Finally, using a xenograft mouse model, we demonstrated that peritumoral administration of TSLP greatly reduced tumor growth accompanied with extensive tumor apoptotic response, which was abolished by tumor cell-specific knockdown of TSLPR. Collectively, our study reveals a novel anti-tumor effect of TSLP via direct promotion of the apoptosis of colon cancer cells, and suggests that TSLP could be of value in treating colon cancer.

A tumor–myeloid cell axis, mediated via the cytokines IL-1α and TSLP, promotes the progression of breast cancer

“…How TSLPR and IL-7Rα expression is regulated during this process remains unknown. A similar finding was reported in colon cancer, where the tumor, but not normal tissues expressed functional TSLPR 13 .…”

“…The possible source of TSLP in these tumor microenvironments was not fully investigated, and the identity of critical TSLP-responding cells was also not clear. Although TSLP has been suggested to play a role in promoting some human cancers mentioned above, several studies have pointed to an anti-tumor role of TSLP in skin, colon, and early stage breast cancers in murine models, emphasizing the need to understand the impacts of TSLP on various cell types in tumor microenvironments 10–13 . The TSLP receptor (TSLPR), composed of TSLPR chain and the interleukin 7 receptor α chain (IL-7Rα), is widely expressed on various immune cells, including B cells, mast cells, macrophages, dendritic cells (DCs), basophils, CD4 + , CD8 + , and regulatory T cells 14,15 .…”

“…TSLP signaling in different immune cell types has been reported to affect various immune responses in mice, and to control related human diseases 1 . Furthermore, TSLPR expression on non-hematopoietic cells has also been seen, including airway and colonic epithelium, with expression regulated by local inflammation 13,16,17 .…”

AllergoOncology – the impact of allergy in oncology: EAACI position paper

“…Thymic stromal lymphopoietin has been shown to block early breast carcinogenesis through the induction of Th2 cells . Thymic stromal lymphopoietin can inhibit colon cancer by inducing apoptosis of cancer cells . Thymic stromal lymphopoietin and Th2 cells also mediate resistance to carcinogenesis in mice with epidermal barrier defect .…”

Yupingfeng Granule Improves Th2‐Biased Immune State in Microenvironment of Hepatocellular Carcinoma through TSLP‐DC‐OX40L Pathway

“…But, in the middle and the late stage, the level of the TSLP expression was correlated with tumor growth and metastasis [12], and tumor-derived TSLP could act on TSLPR + endothelial cells to promote angiogenesis in cervical cancer [41]. Conversely, Di Piazza and Demehri demonstrated that TSLP exerted a tumor-suppressing role in the murine model of skin cancer [26,40] through the engagement of TSLPR [42]. e present study shows for the first time that the expressions of TSLP, TSLPR, and OX40L, which were the key target proteins of the TSLP-OX40L pathway, were increased in the tumor microenvironment of mice bearing with HCC.…”