Obesity and Inflammatory Factors in the Progression of Early-Onset Colorectal Cancer

Round 1

Reviewer 1 Report

Overall, this review is well-constructed and provides valuable insights. However, there are a few areas where further clarification would be beneficial. Firstly, the authors should elaborate on the specific impacts of early obesity exposure on the early onset of colorectal cancer (CRC). Understanding the mechanisms behind this relationship is crucial for developing effective prevention strategies. Secondly, the review could provide a more comprehensive overview of the hormonal aspects related to obesity and CRC. Currently, the evidence in this area seems to be somewhat scattered, and a more cohesive presentation would be helpful. Additionally, while the review highlights three biomarkers and their related pathways in Figure 2, it would be useful to present a more comprehensive picture, summarizing all the adverse effects of obesity on CRC that have been mentioned. This would provide a more holistic understanding of the topic and help readers gain a deeper understanding of the complex relationships between obesity and CRC.

Author Response

Reviewer 1

1. Firstly, the authors should elaborate on the specific impacts of early obesity exposure on the early onset of colorectal cancer (CRC). Understanding the mechanisms behind this relationship is crucial for developing effective prevention strategies.
   3. See addition of section heading 3.1 “Obesity, inflammation and EOCRC” lines 128- 181
2. the review could provide a more comprehensive overview of the hormonal aspects related to obesity and CRC. Currently, the evidence in this area seems to be somewhat scattered, and a more cohesive presentation would be helpful.
   3. See addition section 3.2.1 “Obesity and the Tumor Microenvironment.” Lines 186-230
3. while the review highlights three biomarkers and their related pathways in Figure 2, it would be useful to present a more comprehensive picture, summarizing all the adverse effects of obesity on CRC that have been mentioned. This would provide a more holistic understanding of the topic and help readers gain a deeper understanding of the complex relationships between obesity and CRC.
   1. The main pathways discussed in the paper are referenced within Figure 2a and 2b.

Reviewer 2 Report

The manuscript presents a very interesting topic, the connection between inflammation in obesity and colorectal cancer; however, it requires thorough revision before it can be considered for publication. In my opinion this manuscript is not a review on Obesity and Inflammatory Factors in the Progression of Early Onset Colorectal Cancer, sometimes it seems more like a review on the effects of itaconate.

To review this topic it is necessary to consider the complexity of  factors that lead to chronic low-grade inflammation in the adipose tissue. Among them, there are a vast array of adipokines (resistin, omentin, apelin, vaspin, etc); however, the authors only discuss two of them. There are also many cytokines [TNF-α, interleukin (IL)-6, IL-8 and  monocyte chemoattractant protein (MCP)-1, etc]. In addition, many cell types, including cancer-associated fibroblasts, endothelial cells,  macrophages, dendritic cells, lymphocytes, and other connective tissue constituents participate in the tumor microenvironment. 

In the manuscript several suggestions (not all) have been indicated. Some examples are listed below:

1. Check abbreviations: Abbreviations should be written out in full on first use (in both the abstract and the paper itself) and have to be followed by the abbreviated form in parentheses. After that, use only the abbreviations.

2. References: 45 references are few for this type of review. Several places in the text have been indicated where further references need to be added.

Comments for author File: Comments.pdf

Author Response

Reviewer 2

1. Check abbreviations: Abbreviations should be written out in full on first use (in both the abstract and the paper itself) and have to be followed by the abbreviated form in parentheses. After that, use only the abbreviations.
   1. Abbreviations following first time use revised throughout
2. References:45 references are few for this type of review. Several places in the text have been indicated where further references need to be added.
   1. Reference list increased to 76, see bibliography.
3. I suggest including a brief explanation of M1 and M2 before
   1. Expanded explanation of tumor associated macrophages and M1/M2 macrophages provided, see highlighted additions lines 189-191
4. Grammatical Changes to figure 1, et al, etc.
   1. Revised- removal of period, altered et al.
5. Why the authors talk only about this metabolite? It is necessary to justify this
   1. Justification for highlighting specific metabolites and adipokines provided, see highlighted additions lines 108-112; 197- 200; 227-229
6. I suggest explaining this idea better: “This metabolic transition, mediated by obesity related cytokines, or adipokines, functions as a stressor and promotes tissue damage that can promote neoplasia progression. Once a genetic mutation leads to oncogene activation, inflammation will contribute to cell proliferation, tumor establishment, growth, and metastasis”
   3. See addition of section heading 3.1 “Obesity, inflammation and EOCRC” lines 128- 181
7. I suggest better connecting general ideas about cancer progression with CRC.
   3. See addition of section heading 1 “Obesity, inflammation and EOCRC” lines 128- 181
8. The manuscript presents a very interesting topic, the connection between inflammation in obesity and colorectal cancer; however, it requires thorough revision before it can be considered for publication. In my opinion this manuscript is not a review on Obesity and Inflammatory Factors in the Progression of Early Onset Colorectal Cancer, sometimes it seems more like a review on the effects of itaconate.
   1. Justification for highlighting specific metabolites and adipokines provided, see highlighted additions lines 108-112; 197- 200; 227-229
   2. Addition of Figure 2a
9. To review this topic it is necessary to consider the complexity of factors that lead to chronic low-grade inflammation in the adipose tissue. Among them, there are a vast array of adipokines (resistin, omentin, apelin, vaspin, etc); however, the authors only discuss two of them. There are also many cytokines [TNF-α, interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1, etc]. In addition, many cell types, including cancer-associated fibroblasts, endothelial cells, macrophages, dendritic cells, lymphocytes, and other connective tissue constituents participate in the tumor microenvironment. 
   1. Justification for highlighting specific metabolites and adipokines provided, see highlighted additions lines 108-112; 197- 200; 227-229

Round 2

Reviewer 1 Report

I have no more comments.

Reviewer 2 Report

After justification of the different points, I think that the manuscript can be accepted for publication.