Review Reports - Colitis-Associated Carcinoma: The Quintessential Epithelial Neoplasia Driven by Chronic Inflammation

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review by Drage and Mino-Kenudson is very informative and interesting, describing the main mechanisms regulating the pathogenesis of inflammation-driven neoplasia, with a specific focus on colitis-associated colorectal cancer.

Comment:

The role played by the microbiome, now considered as a central and modifier of colitis-associated colorectal cancer, should be discussed or at least summarized in this review.

Minor comments:

Lines 75-77: please clarify (distinguish) the different cell types present in the colon versus small intestine: absorptive enterocytes for the small intestine, colonocytes for the colon; Paneth cells can be found only in the right colon not distal colon under homeostatic conditions.
Line 155: please specify that cells undergoing apoptosis are cells in the intercryptal space from the colon (not the small intestine).
Line 174 : loss or marked depletion of goblet cells with mucin depletion is also recognized as microscopic feature of chronic colitis. Isn't it?
Lines 196-200: In the classic adenoma-carcinoma sequence of sporadic colorectal cancer, KRAS mutation typically occurs as an earlier event than TP53 mutation, which is usually considered a late event associated with progression to high-grade dysplasia and invasive carcinoma. Please clarify.
Lines 233-234: some words are lacking in these sentences.
Line 266: please correct: LGR5 is receptor (a GPCR) with an extracellular domain rich in leucine-rich repeats that binds R-spondins.
Line 286: “While neutrophils are the best histologic ??? correlate…”
Lines 304-307: this section is difficult to understand. Please clarify.
Line 319: a parenthesis is missing.
Lines 348-350: the sentence needs rewording.

Author Response

Reviewer 1: please clarify (distinguish) the different cell types present in the colon versus small intestine: absorptive enterocytes for the small intestine, colonocytes for the colon; Paneth cells can be found only in the right colon not distal colon under homeostatic conditions.

Please see text edits. This section is limited to describing cell functions, I mention normal and abnormal distribution of Paneth cells later in the text.

Reviewer 1: Line 155: please specify that cells undergoing apoptosis are cells in the intercryptal space from the colon (not the small intestine).

I've added "colonic" to the header for 1.4 to explicitly state that this manuscript is focused on the colon.

Reviewer 1: Line 174 : loss or marked depletion of goblet cells with mucin depletion is also recognized as microscopic feature of chronic colitis. Isn't it?

Loss of goblet cells and mucin depletion is more an indication of active injury (active colitis) and not a key feature of chronicity. Although there is some data that goblet cell differentiation is reduced in IBD, I don't include it here for a few reasons. 1. Goblet cells can be lost due to active inflammation unrelated to IBD. 2. In long-standing IBD, goblet cell differentiation can become increased. Because of these reasons, pathologists do not use loss of goblet cells as an indication of chronic injury.

Reviewer 1: Lines 196-200: In the classic adenoma-carcinoma sequence of sporadic colorectal cancer, KRAS mutation typically occurs as an earlier event than TP53 mutation, which is usually considered a late event associated with progression to high-grade dysplasia and invasive carcinoma. Please clarify.

Please see text edits in track changes. I hope this addresses the point you raised.

Reviewer 1: Lines 233-234: some words are lacking in these sentences.

Thank you for catching that. I have inserted the word "tend" in order to make more sense.

Reviewer 1: Line 266: please correct: LGR5 is receptor (a GPCR) with an extracellular domain rich in leucine-rich repeats that binds R-spondins.

Agree "factor" makes this sentence misleading. I changed the word "factor" to "marker" to more closely reflect how it's being used here.

Reviewer 1: Line 286: “While neutrophils are the best histologic ??? correlate…”

Not sure I understand your meaning, but if looking for clarity: Neutrophils can be identified by HE stain (the only stain used routinely in clinical practice). Identification of IL17-producing CD8 T cells requires multiplex modality not used in routine diagnostic settings.

Reviewer 1: Lines 304-307: this section is difficult to understand. Please clarify

Please see text edits.

Reviewer 1: Lines 348-350: the sentence needs rewording.

Please see text edits.

Reviewer 2 Report

Comments and Suggestions for Authors

The review “Colitis-associated carcinoma: the quintessential epithelial neoplasia driven by chronic inflammation” by Drage and Mino-Kenudson provides an excellent and comprehensive summary of the current knowledge in this field. Inclusion of relevant animal models would have further strengthened the review, but I understand that this is beyond the scope of this review.

While the manuscript is very well written, the figures could be improved. In several instances, scale bars are missing, the legend for Figure 2I is absent, and it is unclear whether serrated tumor lesions are depicted in Figure 2G and/or 2H. Highlighting the features described in the legends, for example by using arrows, would help to guide the reader. In addition, in Figure 1 it is unclear whether the apoptotic features shown relate to the normal colon or to injury. It is also not clear whether Figure 1 encompasses all major features of intestinal inflammation.

I am not an expert in this area, but are Paneth cells not restricted to the small intestine?

Finally, a minor point concerns the described function of Notum in CRC (line 193), which is unclear and may benefit from clarification.

Author Response

Thank you for your supportive comments. I have addressed many of the issues you raised here, inserting the missing (I) in the legend for Figure 2, and inserting arrows to highlight the specific points being illustrated.

Figure 1 shows intercrypt apoptosis in normal colon. Figure 1 does not encompass all major features of intestinal inflammation, but is rather focused on demonstrating the histologic features specific to chronicity (recurrent injury). There are many other types of injury (mechanical, ischemic, drug-related, fungal, bacterial, viral infections) that are outside the scope of our review here.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thanks to the authors for the corrections and revisions.

I still think it would have been relevant to summarize the state of the literature on the role of microbiota in inflammation-induced cancer.