Interleukin-33: Friend or Foe in Gastrointestinal Tract Cancers?
Round 1
Reviewer 1 Report
The role of interleukin-33 (IL-33) in gastrointestinal tract cancers is not yet fully understood, but ongoing research suggests its involvement. IL-33 is known to be involved in inflammatory and immune responses, and these processes have been implicated in cancer development and progression, and IL-33 may influence the pathogenesis of gastrointestinal cancers. In this review, the findings to date on the positive and negative effects of IL-33 in gastrointestinal cancers are summarized. The results of these studies suggest that IL-33 may influence the development and progression of gastrointestinal cancers, but that its role is complex and varies by disease state. This review covers early reports on IL-33 as well as the most recent findings and will be useful to readers who want an overview of this area.
Main points
Introduction: Signalling by IL-33 and ST2 has been studied in the context of inflammatory and autoimmune diseases, particularly in relation to cardiac disease (Nat Rev Drug Discov. doi: 10.1038/nrd2660). As the authors point out, the role of IL-33 in cancer has been less well clarified. They seem to use references 11-13 as a basis for explaining why they came to focus on the relevance of IL-33 for cancer, but the explanation seems to be somewhat lacking. Could the authors be more specific about the content of these cited papers?
In the chapter "2.Method", the content after section 2.3 is not a description of the 'method', but of the main topics of this review; sections 2.3 onwards should be numbered as chapter 3, separate from chapter 2. This is the first part where the IL-33/ST2 system is mentioned, but it would be easier to understand if basic findings about this signaling pathway system were summarised. Alternatively, the IL-33/ST2 system could be explained in more detail in the 'Introduction'. The positive and negative role of the IL-33/ST2 system in cancer progression in gastric and colorectal cancers is understood from the examples of studies listed in the main text. On the other hand, it is not clear how IL-33 is produced in these cancer tissues. What level of knowledge exists in this regard? My overall impression is that the description of the molecular mechanism of the effect of IL-33 is rather brief. A more in-depth explanation would be helpful.
Minor corrections
It would be better to include relevant reference numbers in the figure legends.
Author Response
We thank the reviewer and we add a section that better explains the rationale that sparked our interest in IL-33 in tumors of the gastrointestinal tract. We also add as required, IL-33 secreting cell types and their possible role in tumorigenesis.
Finally we numbered the chapters in the correct order.
Reviewer 2 Report
Interleukin-33: Friend or Foe in Gastrointestinal Tract Cancers?
The above titled manuscript reviewed the role of IL-33 in GI tract cancers. The systematic review is well written and the authors have clearly narrated the facts from the selected articles. The tables and figures are able to aptly convey the dual role of IL-33 in GI tract cancers. However, Table.2, third raw is not complete and please correct the same. Therefore, I would suggest accepting the manuscript in this form after that minor correction.
Author Response
We thank the Reviewer for the positive comments and we corrected the missing part of table 2.
Reviewer 3 Report
Very interesting and comprehensive review about the role of IL-33 in the oncological disorders of the gastrointestinal tract. The focus of this review is on the role of IL-33/ST2 axis in onset and progression of gastrointestinal cancer in general as well as colorectal cancer, gastric cancer, and esophageal cancer particularly. In total, 79 original studies were included in this review.
The review is accompanied by very informative figures on the pathogenetic mechanisms of IL-33 in the promotion of gastric cancer and colorectal cancer.
Comment:
This reviewer proposes to subdivide the information contained in section 2.3. IL-33 in Gastric Cancer, 2.4. IL-33 in Colorectal Cancer, and 2.5. IL-33 in Esophageal Cancer in subsections with subtitles describing effects of IL-33 on the cellular level or effects of IL-33 in animal models or therapeutic modulation of IL-33 in order to make these three sections more focused and constructed.
Author Response
We thank the Reviewer for the positive comments. We numbered the chapters in the correct order and also we prepared the sections as suggested
