The Effects of Resveratrol on Prostate Cancer through Targeting the Tumor Microenvironment
Round 1
Reviewer 1 Report
The review article entitled “The Effects of Resveratrol on Prostate Cancer through Targeting the Tumor Microenvironment” is focused on summarize the recent advancement in RSV-inhibited prostate cancer as well as the underlying molecular mechanisms, especially its effect through TME. There are a lot reviews article on anti-cancer properties Resveratrol e.g. 10.1530/ERC-13-0171, https://doi.org/10.1093/jn/133.7.2440S, 10.1158/1940-6207, 10.3390/ijms18122589, DOI: 10.1530/ERC-13-0171, https://doi.org/10.1080/10408398.2016.1263597. There are various reports in the literature on the possibility of using revestaol in an effective anti-cancer therapy. Much of the work on resveratrol and cancer comes from in vitro studies looking at resveratrol actions on cancer cells and pathways. There are comparatively fewer studies that have investigated resveratrol treatment and cancer outcomes in vivo. In most of the clinical trials, the major obstacle presented was resveratrol’s poor bioavailability. Therefore, research is being conducted on the possibility of using RSV in combination therapies, e.g. with zinc (10.4161/cc.29334), gold (10.2147/IJN.S204443) or Quercetin (10.3390/cancers12082141) or the search for new analogues. The review of Resveratrol analogues is quite extensive, which proves the great interest in this topic among researchers (https://doi.org/10.1016/j.ejmech.2020.112356). In addition to the comment above, I have two minor remarks:
- All figures are illegible. Letters and structure of compounds are too small.
- In the last sentence in the chapter: "Conclusions and Perspectives" - the wrong abbreviation for RSV was used.
Author Response
The review article entitled “The Effects of Resveratrol on Prostate Cancer through Targeting the Tumor Microenvironment” is focused on summarize the recent advancement in RSV-inhibited prostate cancer as well as the underlying molecular mechanisms, especially its effect through TME. There are a lot reviews article on anti-cancer properties Resveratrol e.g. 10.1530/ERC-13-0171, https://doi.org/10.1093/jn/133.7.2440S, 10.1158/1940-6207, 10.3390/ijms18122589, DOI: 10.1530/ERC-13-0171, https://doi.org/10.1080/10408398.2016.1263597. There are various reports in the literature on the possibility of using resveratrol in an effective anti-cancer therapy. Much of the work on resveratrol and cancer comes from in vitro studies looking at resveratrol actions on cancer cells and pathways. There are comparatively fewer studies that have investigated resveratrol treatment and cancer outcomes in vivo. In most of the clinical trials, the major obstacle presented was resveratrol’s poor bioavailability. Therefore, research is being conducted on the possibility of using RSV in combination therapies, e.g. with zinc (10.4161/cc.29334), gold (10.2147/IJN.S204443) or Quercetin (10.3390/cancers12082141) or the search for new analogues. The review of Resveratrol analogues is quite extensive, which proves the great interest in this topic among researchers (https://doi.org/10.1016/j.ejmech.2020.112356). In addition to the comment above, I have two minor remarks:
- All figures are illegible. The letters and structure of compounds are too small.
To improve the legibility, we have replaced all three figures with larger letters and higher resolution.
- In the last sentence in the chapter: "Conclusions and Perspectives" - the wrong abbreviation for RSV was used.
That was a careless mistake and it has been corrected. Thanks.
Reviewer 2 Report
This is a well-written manuscript detailing the effects of Resveratrol on Prostate Cancer and its tentative targeting of the tumor microenvironment. The authors have performed a thorough review of the available literature to bring the current knowledge about the subjects for the readers. Although the manuscript captures prostate specific information, some information about a general role of resveratrol in cancer tumor microenvironment could potentially be added in the form of a table to enhance the information provided for the readers. The manuscript could also benefit from more updated references. The provided figures although very detailed could be provided more clearly as currently it is very difficult to ascertain what is being depicted. If a better resolution images will be included in the finalized manuscript then this could be neglected.
Overall this manuscript is a well drafted piece of information and will benefit the reader significantly.
Author Response
This is a well-written manuscript detailing the effects of Resveratrol on Prostate Cancer and its tentative targeting of the tumor microenvironment. The authors have performed a thorough review of the available literature to bring the current knowledge about the subjects for the readers. Although the manuscript captures prostate specific information, some information about a general role of resveratrol in cancer tumor microenvironment could potentially be added in the form of a table to enhance the information provided for the readers. The manuscript could also benefit from more updated references. The provided figures although very detailed could be provided more clearly as currently it is very difficult to ascertain what is being depicted. If a better resolution images will be included in the finalized manuscript then this could be neglected.
Overall this manuscript is a well-drafted piece of information and will benefit the reader significantly.
Thanks for your so positive comments, and we truly hope that the readers will benefit from reading our paper.
Reviewer 3 Report
In this review, the author summarized the recent development of resveratrol as a therapeutic reagent for prostate cancer. They mainly discuss the anti-cancer properties of resveratrol by targeting the tumor microenvironment to inhibit prostate cancer initiation, proliferation and metastasis. Overall, this is a well-written paper, it would be great to improve the figure resolution.
Author Response
In this review, the author summarized the recent development of resveratrol as a therapeutic reagent for prostate cancer. They mainly discuss the anti-cancer properties of resveratrol by targeting the tumor microenvironment to inhibit prostate cancer initiation, proliferation and metastasis. Overall, this is a well-written paper, it would be great to improve the figure resolution.
Thank you for your so positive comments. To improve the legibility, we have replaced all three figures with larger letters and higher resolution.
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
In this review, the authors were able to give a good summary of the effects of resveratrol (RSV) on prostate cancer, related to the influence of this polyphenol on the tumor microenvironment (TME). Extensive research has been done using RSV in prostate cancer models both in vivo and in vitro and several studies have demonstrated the efficacy in the use of RSV to induce cell cycle arrest, block of the proliferation and reduction in the migratory behavior in several cancer, including prostate cancer.
Overall the review is well written and the authors were able to reach the aim they stated in the title. however there are very few point that, in my opinion, need to be addressed:
1- paragraph 2: the title of the paragraph stated "RSV Inhibits Prostate Cancer Initiation by Targeting the TME". The authors in this paragraph talked more of how prostate cancer start and progress than the effects of RSV, that are described in the last few lines of the paragraph. I suggest to shorten a little the first part and emphasize more the role of RSV in prostate cancer, related to the TME, or restructure the paragraph as a general description of what the TME is in relation to prostate cancer.
2- The rest of the paragraphs are well structured and I think nothing need to be changed.
3- The figures could be improved in size and resolution.
Author Response
Comments and Suggestions for Authors
In this review, the authors were able to give a good summary of the effects of resveratrol (RSV) on prostate cancer, related to the influence of this polyphenol on the tumor microenvironment (TME). Extensive research has been done using RSV in prostate cancer models both in vivo and in vitro and several studies have demonstrated the efficacy in the use of RSV to induce cell cycle arrest, block of the proliferation and reduction in the migratory behavior in several cancer, including prostate cancer.
Overall the review is well written and the authors were able to reach the aim they stated in the title. however there are very few point that, in my opinion, need to be addressed:
1- paragraph 2: the title of the paragraph stated "RSV Inhibits Prostate Cancer Initiation by Targeting the TME". The authors in this paragraph talked more of how prostate cancer start and progress than the effects of RSV, that are described in the last few lines of the paragraph. I suggest to shorten a little the first part and emphasize more the role of RSV in prostate cancer, related to the TME, or restructure the paragraph as a general description of what the TME is in relation to prostate cancer.
Thank you for your positive comments. We completely agree with what you suggested. Therefore, we did two things to address your concerns: (1) we have changed this specific subtitle into "The Role of RSV in TME-mediated prostate cancer initiation,” and (2) we have added the following sentences at the beginning of the paragraph: "Since the cancer-preventive effects of RSV were first reported in 1997 [22], both epidemiological and case-controlled studies have demonstrated that RSV and/or consumption of foods/drinks with high levels of RSV can reduce prostate cancer incidence [40]. These findings suggest that RSV could potentially inhibit prostate cancer initiation". This way, we assure the readers that RSV is capable of reducing prostate cancer incidence before introducing the effect of RSV on the tumor microenvironment in prostate cancer.
2- The rest of the paragraphs are well structured and I think nothing need to be changed.
Thank you. We have therefore kept the rest without any major change.
3- The figures could be improved in size and resolution.
To improve the resolution of the figures, we have increased their sizes, as you suggest.
Reviewer 2 Report
The authors discuss the relationship between the cancer microenvironment and resveratrol in the development of prostate cancer.
This review focuses solely on resveratrol, which leads to repetition of similar information. A review should provide a broad overview, impart knowledge, and spark research ideas. In addition, some polyphenols should be discussed, at least. Furthermore, the author discusses a single bioactive small molecule but does not expand upon the target molecule, which results in mere enumeration of information.
For these reasons, I cannot help but feel that this paper is somewhat lacking, and as such, is not ready for publication.
Author Response
The authors discuss the relationship between the cancer microenvironment and resveratrol in the development of prostate cancer.
This review focuses solely on resveratrol, which leads to repetition of similar information. A review should provide a broad overview, impart knowledge, and spark research ideas. In addition, some polyphenols should be discussed, at least. Furthermore, the author discusses a single bioactive small molecule but does not expand upon the target molecule, which results in mere enumeration of information.
For these reasons, I cannot help but feel that this paper is somewhat lacking, and as such, is not ready for publication.
Thank you for your candid comments and suggestions. We agree with all your concerns. Therefore, we have (1) addressed why we have only focused on the RSV in this review article, and (2) added a substantial amount of information to improve the article’s ability to "provide a broader overview, impart knowledge, and spark research ideas.”
To address the first point, we added the following in the Conclusions and Perspectives section: "As one of the review articles in this special issue titled “Mechanism and Target of Resveratrol and Its Analogs in the Reorganization of the Tumor Microenvironment”, we specifically focused our attention on how RSV affects prostate cancer initiation and progression by targeting the tumor microenvironment. Since RSV shares some similar effects with its derivatives/analogs, we have discussed these analogs occasionally but purposely saved the details for other articles in this special issue". In addition, we have also added a few sentences in the Introduction: "Because of these advantages, RSV stands out as a potential therapy for prostate cancer, either by itself or in combination with other drugs. As part of this special issue, our review provides an in-depth examination of current knowledge of the effects of RSV on the TME in prostate cancer initiation, proliferation, and metastasis". These remind the readers of what we are going to focus on and why we did so.
To address the second point, we have included the effects of some RSV analogs when necessary. For example, we added the following in different sections:
In section 3.1 (RSV inhibits prostate cancer proliferation by interrupting stroma-tumor cell communication) when we discuss RSV's effect on cancer cell proliferation we added "Another naturally occurring stilbene piceatannol has been shown to have inhibitory effects on the IL-6/JAK/STAT3 pathway. For example, orally administered piceatannol can lower the serum levels of IL-6 significantly in mice accompanied by STAT3 inactivation. Additionally, by targeting cyclin A, cyclin D1, CDK2, and CDK4 piceatannol can also arrest the DU145 prostate cancer cells at their G1 phase with activated Bid, Bax, Bik, Bok, and Fas and decreased Mcl-1 and Bcl-xL. These findings altogether suggest that RSV as well as its homologs exert their inhibitory effect on prostate cancer cell proliferation by not only reducing the number of CAFs and consequently the CAF-secreted IL-6 but also inhibiting IL-6-mediated downstream signaling pathways".
In section 3.2 (RSV inhibits cancer cell proliferation by affecting Hypoxic conditions of the TME) we added "Similar to RSV, piceatannol can increase prostate cancer cell release of cleaved caspase-8, -9, -7, -3, and cytochrome c from the mitochondria to the cytosol.
In section 4.2 (Resveratrol inhibits Prostate Cancer metastasis by Targeting the Extracellular Matrix) we added "Additionally, the RVS analog piceatannol affects the mRNA levels of MMP-9 and the protein levels of MMP-2 similarly".
In section 4.3 (Inhibitory effects of RSV on Prostate Cancer Cell Bone Metastasis) we added "RSV and its analog HS-1793 are capable of inhibiting both hypoxia-induced VEGF expression and prostate cancer cell migration [115] (Figure 3). In addition, RSV either alone or in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can inhibit the VEGF/VEGFR2 axis in vivo [104]. Furthermore, results from both in vitro and in vivo models showed that the other members of the RSV family including piceatannol, pinosylvin, and 3,40,5-trimethoxy-trans stilbene can also inhibit the VEGF-mediated signaling pathways. Intriguingly, the repressive effect of piceatannol on VEGF-mediated cell proliferation is even stronger than RSV".
In section 4.4 (RSV inhibits Immune Cell-mediated Prostate Cancer Metastasis), we added "in addition, piceatannol is also capable of decreasing the macrophage counts in mouse mammary cancer".
Finally, we have added the following two new parts to the Conclusions and Perspectives section to address the importance of (1) studying the role of RSV conjugates and (2) identifying RSV-interacting molecules:
"In addition, results from in vivo experiments demonstrated that orally delivered RSV appears in the bloodstream quickly and the overwhelming majority of the absorbed RSV is conjugated into mono-sulfate RSV in about 10 minutes [ 149]. Therefore, most of the biological effects observed in both animals and humans are likely from the conjugated RSV. However, little attention has been paid to the conjugated RSV. Given the advancement in RNA-seq technology, it becomes much easier to differentiate the distinct biological effects of differently conjugated RSV systemically".
"Furthermore, RSV exists as either the trans- or the cis-isoforms, and it is the trans-RSV that possesses the effects discussed in this review [150]. Further chemical analysis indicates that these isoforms are geometrically different from each other, each with its absorption spectrums [151]. Therefore, the biological effects of RSV are the results of the specific interaction between RSV and biomolecules in the cells [152]. How can we speed up the identification of more RSV-interacting molecules? Answers to these questions and a better understanding of the underlying molecular mechanisms in how RSV inhibits prostate cancer progression by interrupting stromal-cancer cell communication will pave the road toward the application of ESV as both a cancer preventive and therapeutic reagent.".
