Functions and Therapeutic Use of Heat Shock Proteins in Hepatocellular Carcinoma
, Christophe F. Grosset 3,* and Buddhi Prakash Jain 1,*
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis article reviews the role of heat shock proteins and clusterin in hepatocellular carcinoma (HCC) and their progress as therapeutic targets. Targeted therapies against molecular chaperones may lead to more effective treatments for patients with HCC that were previously difficult to treat. However, the article suffers from the following problems: 1. What is the innovation of the article in comparison with existing related articles (e.g., https://doi.org/10.1002/ijc.29723)? 2. Heat shock proteins have many normal physiologic effects. Have any considerations been made for the adverse effects of inhibitors that target heat shock proteins? 3. Has any consideration been given to the fact that many of the drugs in the article that target heat shock proteins have multifaceted anti-tumor effects? 4. Do heat shock proteins have a unique role in HCC compared to tumors at other sites? 5. A table can be generated for the classification and role of the heat shock protein family. As a review, there are not enough reference articles on heat shock proteins. 6. The pictures in the article are not clear enough.
Author Response
Reviewer 1:
- What is the innovation of the article in comparison with existing related articles (e.g., https://doi.org/10.1002/ijc.29723)?
Response: Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death and recently heat shock proteins are found to be a potential target treatment of various cancers. Our article delineates the profound role of HSPs in progression and a potential target for treating HCC. There are many articles in the literature that describe the relationship between the heat shock proteins and cancer in general but no article describes the implications of HSPs specifically in hepatocellular carcinoma (HCC), even the referred article in the comment mainly focusses on clusterin, Hsp27, Hsp70 and Hsp90 in HCC, while our article discusses more comprehensively about all the classes of HSPs including, Hsp110, Hsp90, Hsp70, Hsp60, Hsp27, Hsp20 and clusterin and their implication in HCC. The present manuscript also dealt with more recent updated information related to the topic. The representation of the facts is clearer and more detailed.
- Heat shock proteins have many normal physiologic effects. Have any considerations been made for the adverse effects of inhibitors that target heat shock proteins?
Response: Thank you for the comment. Under physiological conditions the expression of HSPs is negligible which increases drastically in stressed condition as well as in cancer cells. With the help of elevated level of HSPs the cancer cells can evade anti-growth signals, apoptosis while promote cell proliferation (Heat shock Heat Shock Proteins Promote Cancer: It's a Protection Racket Stuart K. Calderwood 2016). Targeting HSPs like HSP90 can cause targeted damage specifically to tumor cells but are less toxic to normal cells (Recent advances in heat shock proteins in cancer diagnosis, prognosis, metabolism and treatment Yang a b c, Haiyan Xiao a b c, Li Cao a b) Therefore, many HSP inhibitors have entered clinical trials to treat malignancies. Owing to the comment, we have added these lines in the manuscript.
- Has any considération been given to the fact that many of the drugs in the article that target heat shock proteins have multifaceted anti-tumor effects?
Response: As the signalling pathways for various cancers are same and all require HSPs for their sustainable growth, the durgs that target HSPs have multifaceted anti-tumor effects. We have added the its examples in the manuscript after your suggestion.
- Do heat shock proteins have a unique role in HCC compared to tumors at other sites?
Response: Elevation in in the expression of HSPs leads to the activation of various signaling pathways involved in cell proliferation, metastasis, differentiation and apoptosis which are common to all the malignancies. In this review we have tried to summarize all the ongoing treatment strategies, for HCC which involve HSPs and are under preclinical and clinical trial.
- A table can be generated for the classification and role of the heat shock protein family. As a review, there are not enough reference articles on heat shock proteins.
Response: A Table has been added as per suggestion. Also, number of references increased with more focuses on the clinical literature.
- The pictures in the article are not clear enough.
Response: We have improved the quality of the uploaded images.
Reviewer 2 Report
Comments and Suggestions for AuthorsReview Livers: livers-2809395. Paul et al.
COMMENTS:
General Comments: I praise the authors in choosing the topic which is now becoming very important in the medical communities, science, and the researchers, as one of the upcoming and could be the major public health issues worldwide. Despite of its (genes in HCC) multifaceted etiology and the pathophysiology, the authors should have been more careful about only the therapeutic aspects of the HSPs and or Clustering, authors have more ways to define in specifically not only on gene based, but also the pathways that they involved I, and the with my following recommendation, this article could have much been improved.
The specific comments are:
In Abstract and the Introduction of the review:
Being a “Review” article what were the review strategies which were undertaken and how it was conducted, and information gathered (rationale in a simple one para at the end of Introduction, and line in the abstract) or at the very beginning is important and must.
In Introduction:
Line 32- 33: Need a reference as mentioned the facts.
Line 38-41: Redundant. Not necessary. Directly go to Next Sentences that starts with Chaperones.
Line 50: put “a” in front of Part.
Line 58-60: Why such citing of the diseases. Any remembrances that looks like they have if you wish to stay within, a correlation of its disease pathophysiology mut be mentioned.
Figure 1 and 2: These figures must also be improved with signaling processes involved in the disease progression and who controls whom with an indication is required. That is true also for the Section 2 and 3 (Line 146-466). More graphics that of laundry lists are required. Otherwise, readers will lose interest.
Line 467; Table -1: Table should be in a Tab-delimited format not boxed. Also notices that most of the references about the HSPs are in vitro, but not a good representation of clinical references. Please review the clinical reviews and the research and update them.
Additional notes: With 90% cases of the HCC undetected in developing and underdeveloped countries, what could be public health strategies to combat such health issues. With the rise of NAFLD (MAFLD now) that ultimately leads to HHC in most of the cases, has to also to be dealt herein.
In Conclusion:
(Line 468-507): This section needs to be thoroughly remodeled/updated align to the clinical impotence of this review and its general application in the clinics, as it has now become more clinically relevant in making it more impacting.
In Financial Support/Sponsorship as well as Conflict of interests:
As the authors receives funds from many charities and Many Foundations, and the other Govt. entities looks like. There should also be declaration as disclaimer that the authors don’t have and had any financial benefit from those Foundations and Companies, or if there is any.
Author Response
The specific comments are:
In Abstract and the Introduction of the review:
Being a “Review” article what were the review strategies which were undertaken and how it was conducted, and information gathered (rationale in a simple one para at the end of Introduction, and line in the abstract) or at the very beginning is important and must.
Response: Thank you for the comment. We have added a paragraph in the introduction section.
In Introduction:
Line 32- 33: Need a reference as mentioned the facts.
Response: Refence has been added.
Line 38-41: Redundant. Not necessary. Directly go to Next Sentences that starts with Chaperones.
Response: As per instructions we have removed the redundant lines.
Line 50: put “a” in front of Part.
Response: Correction has been made as per the suggestion.
Line 58-60: Why such citing of the diseases. Any remembrances that looks like they have if you wish to stay within, a correlation of its disease pathophysiology mut be mentioned.
Response: Correlation has been mentioned as per suggestions.
Figure 1 and 2: These figures must also be improved with signaling processes involved in the disease progression and who controls whom with an indication is required. That is true also for the Section 2 and 3 (Line 146-466). More graphics that of laundry lists are required. Otherwise, readers will lose interest.
Response: We have now improved the quality of the images.
Line 467; Table -1: Table should be in a Tab-delimited format not boxed. Also notices that most of the references about the HSPs are in vitro, but not a good representation of clinical references. Please review the clinical reviews and the research and update them.
Response: Table has been updated as per suggestions. More clinical references now added.
Additional notes: With 90% cases of the HCC undetected in developing and underdeveloped countries, what could be public health strategies to combat such health issues. With the rise of NAFLD (MAFLD now) that ultimately leads to HHC in most of the cases, has to also to be dealt herein.
Response: We have added a paragraph in the discussion section. Thank you.
In Conclusion:
(Line 468-507): This section needs to be thoroughly remodeled/updated align to the clinical impotence of this review and its general application in the clinics, as it has now become more clinically relevant in making it more impacting.
Response: Conclusion part has been revised
In Financial Support/Sponsorship as well as Conflict of interests:
As the authors receives funds from many charities and Many Foundations, and the other Govt. entities looks like. There should also be declaration as disclaimer that the authors don’t have and had any financial benefit from those Foundations and Companies, or if there is any.
Response: We have added a line the financial support section.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThe author answered my questions and made modifications. I am satisfied. Heat shock proteins play an important role in emergency situations, so I believe that inhibiting heat shock proteins has adverse effects. Of course, this has little to do with this article.
Reviewer 2 Report
Comments and Suggestions for AuthorsThanks to the authors for considering the required changes while revising he manuscript. Job well done now.
