The Complex Tumor Microenvironment in Ovarian Cancer: Therapeutic Challenges and Opportunities

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript by Garlisi and co-authors is a review of the current literature on the role of tumor microenvironment as it relates to the success of chemotherapies in ovarian cancer. The article is well-organized and illustrated. The emphasis on the underlying role of neovascularization, interstitial fluid pressure, and immunosuppression is a fairly comprehensive view on the prominent microenvironmental factors that are thought to influence treatment outcomes. There are no critique points to be addressed.

Comments on the Quality of English Language

A few typos are found throughout the text.

Author Response

We thank the reviewer for the careful review of our paper and for their enthusiasm for the submission.

Reviewer 2 Report

Comments and Suggestions for Authors

The paper discusses TME and its properties, challenges and potential therapeutics. Although it is well written, I feel that it is quite broad and so lacks a focus. 

Additionally, the paper does not offer much novelty. Some of the aspects described here have already been published elsewhere very recently as review articles in the recent years (and these articles have not been cited here either).

Topics such as: Cathepsins D and L (in angiogenesis), galectin-1 (angiogenesis), VEGF (and therapeutics), mechanistic immunosuppressive role of the tumour vasculature ,etc are some examples of recent works in ovarian cancer.

 

Nevertheless, I think there is still an opportunity to improve this manuscript by adding discussions on the above as well as adding a future perspective (perhaps along with the conclusion). Moreover, a table summarising the latest small molecule inhibitors that are in investigation either in vitro/vivo or  current/ongoing clinical trials and outcomes would be recommended. Another table illustrating the different types of ovarian cancers e.g. HGSC, would be beneficial for the readers.

 

I believe if the above is addressed, the manuscript would bring much more impact to the readership.

Author Response

 

 

Topics such as: Cathepsins D and L (in angiogenesis), galectin-1 (angiogenesis), VEGF (and therapeutics), mechanistic immunosuppressive role of the tumour vasculature ,etc are some examples of recent works in ovarian cancer.

We have included information on all of these molecules and factors and thank the reviewer for their constructive suggestions 

Nevertheless, I think there is still an opportunity to improve this manuscript by adding discussions on the above as well as adding a future perspective (perhaps along with the conclusion). Moreover, a table summarising the latest small molecule inhibitors that are in investigation either in vitro/vivo or  current/ongoing clinical trials and outcomes would be recommended. Another table illustrating the different types of ovarian cancers e.g. HGSC, would be beneficial for the readers.

We have included a future perspectives as part of the conclusions and have included a table on the different forms of ovarian cancer.  Thank you for the suggestions.

Reviewer 3 Report

Comments and Suggestions for Authors

Overall, this manuscript covers a topic of relevant interest, although there are a lot of reviews now considering the TME so I think this needs a few edits to make it a valuable addition. My major points:

- the authors might benefit from referencing more prior reviews of the TME, which although not ovarian specific still lend important insight into the area.

- the ECM is very poorly covered, there are proteomic studies uncovering a role for the ECM in the ovarian TME so this should be covered.

Minor points:

- there are a lot of punctuation and language errors. Although overall understanding is communicated, the authors need to proof-read this to ensure the language is previse. One example is "described as being in 1 million DNA bases" (line 245) which does not make sense, and authors should avoid personal terms like "we".

- I am not sure I agree with the description of M1 as "normal" and M2 as "pathogenic" (lines 149-150). These are physiological states which are dysfunctional in the TME. This needs clarifying.

- Similar points are made on TAMs in lines 256, 286-305. The authors could avoid repetition with some restructuring. The abbreviation TAM is defined multiple times.

- References are needed in line 207 when referring to previous reviews.

- section 5.2 introduces barriers that "inhibit therapeutic success". The first sentence outlines that TME "facilitate tumorigenesis and metastasis" - that is not discussing therapeutic success.

- similarly line 308-309 discussed TME "evading the immune system" but this seems like a language error - the TME facilitates cancer cells to evade the immune system?

- figure 2 has ECM degradation as a feature "inhibiting therapeutic efficiency"? How? Maybe more detail on ECM would help this.

 

Comments on the Quality of English Language

This is OK but there a lot of review articles on the TME and so I would expect reviews to be precise, this needs editing before publication.

Author Response

Overall, this manuscript covers a topic of relevant interest, although there are a lot of reviews now considering the TME so I think this needs a few edits to make it a valuable addition. My major points:

- the authors might benefit from referencing more prior reviews of the TME, which although not ovarian specific still lend important insight into the area.

We have included more discussion and reviews on the TME.  

- the ECM is very poorly covered, there are proteomic studies uncovering a role for the ECM in the ovarian TME so this should be covered.

We have included a more robust discussion on the components and roles of the ECM in tumorigenesis - thank you for the suggestion on this aspect.

Minor points:

- there are a lot of punctuation and language errors. Although overall understanding is communicated, the authors need to proof-read this to ensure the language is previse. One example is "described as being in 1 million DNA bases" (line 245) which does not make sense, and authors should avoid personal terms like "we".

We have carefully evaluated the paper for spelling/grammar issues and made the appropriate revisions.

- I am not sure I agree with the description of M1 as "normal" and M2 as "pathogenic" (lines 149-150). These are physiological states which are dysfunctional in the TME. This needs clarifying.

We have clarified this information.

- Similar points are made on TAMs in lines 256, 286-305. The authors could avoid repetition with some restructuring. The abbreviation TAM is defined multiple times.

We have revised our discussion on TAMs to reduce repetition and improve clarity.

- References are needed in line 207 when referring to previous reviews.

We have included more references for the review papers.

- section 5.2 introduces barriers that "inhibit therapeutic success". The first sentence outlines that TME "facilitate tumorigenesis and metastasis" - that is not discussing therapeutic success.

We have revised this section to improve clarity.

- similarly line 308-309 discussed TME "evading the immune system" but this seems like a language error - the TME facilitates cancer cells to evade the immune system?

We have made revisions to this section.

- figure 2 has ECM degradation as a feature "inhibiting therapeutic efficiency"? How? Maybe more detail on ECM would help this.

We have added significant additional information on the ECM components and roles in tumorigenesis.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors resubmitted their revised version however, my comments were not addressed adequately:
1. the citations the authors have added on galectin-1 and cathepsins are not specific to ovarian cancer. There are publications since 2018 on cathepsin D, L and galectin-1 that specifically address angiogenesis in ovarian cancer. I would recommend authors to address these before submitting.

2. there is no table in the manuscript as per their response?

Author Response

We have increased the discussion on Cathepsins and galectins to specifically address their role in ovarian tumor angiogenesis

We have included a table listing targeted therapies and small molecule inhibitors in ovarian cancer.

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

All have been addressed.