Expression and Signaling Pathways of Nerve Growth Factor (NGF) and Pro-NGF in Breast Cancer: A Systematic Review
, Domenico Arcuri 3, Francesca Vozzo 3, Antonio Malvaso 4, Alberto Montesanto 5,† and Raffaele Maletta 1,2,†
Round 1
Reviewer 1 Report
This well-written review by Bruno et al. provides a comprehensive overview of NGF signaling pathways in breast cancer. In this context, the authors first briefly present the classification, risk factors, treatment strategies, and classical prognosis of breast cancer. They then describe the molecular mechanism of NGF signaling and NGF receptors and their effects on breast cancer cell proliferation, survival, invasion and metastasis. The expression of NGF, pro-NGF and their receptors, NGFR/p75NTR and TrkA, during breast cancer development and progression is described, which could represent a potential biomarker for breast cancer diagnosis, but also useful for differential diagnosis between different types of breast cancer. The authors effectively synthesize over 100 publications of data and reviews on this topic in a clear and concise review. Although I appreciated section 5 on the mechanisms of NGF-induced mitogenesis, anti-apoptosis, angiogenesis, and metastasis of breast cancer cells, an area that I believe deserves further study, an illustration could be added to show the action and involvement of NGF/NGFR in these cellular processes. On the other hand, the paragraph on the NGF signaling pathways as a therapeutic target (page 11) needs to be better explained and the relationship with NF-kB1 better defined.
There are several typos and spelling mistakes that need to be corrected throughout the text, for example:
Page 9- line 400 "NGF and its receptors seems" should be corrected to "NGF and its receptors seem".
Page 11- line 526 "against NGF reduced the cell proliferation" should be replaced by "against NGF reduce the cell proliferation". line 527 "increase apoptosis and an inhibit tumor angiogenesis" should be replaced by "increase apoptosis and inhibit tumor angiogenesis".
Author Response
Comment. Although I appreciated section 5 on the mechanisms of NGF-induced mitogenesis, anti-apoptosis, angiogenesis, and metastasis of breast cancer cells, an area that I believe deserves further study, an illustration could be added to show the action and involvement of NGF/NGFR in these cellular processes.
Response. Thank you to the reviewer for this feedback. We have now added the illustration.
Comment. On the other hand, the paragraph on the NGF signaling pathways as a therapeutic target (page 11) needs to be better explained and the relationship with NF-kB1 better defined.
Response. Thank you to the review for this feedback. We have now better explained the relationship between NGFR/p75NTR and NF-kB also in this paragraph (marked in red). Also we have reduced the length of the “Treatments and prognosis” paragraph accordingly to the suggestion of the other reviewer.
Comment. There are several typos and spelling mistakes that need to be corrected throughout the text, for example:
Page 9- line 400 "NGF and its receptors seems" should be corrected to "NGF and its receptors seem".
Page 11- line 526 "against NGF reduced the cell proliferation" should be replaced by "against NGF reduce the cell proliferation". line 527 "increase apoptosis and an inhibit tumor angiogenesis" should be replaced by "increase apoptosis and inhibit tumor angiogenesis".
Response. Thank you to the review for this feedback. We have now corrected the typos and spelling mistakes.
Reviewer 2 Report
The overview conveys very basic knowledge for laypersons. However, the added value of such a lengthy introduction is questionable as it doesn't really relate to the role of NGF. In particular, paragraph 2.4. "Treatments and prognosis" is an unbalanced and simplified compilation of basic information (e.g. that chemotherapy can cause hair loss; or the information on radiotherapy starts with intraoperative radiotherapy, 3D conformal radiotherapy, does not provide key information that radiotherapy is an integral part of a breast-conserving surgery is and in which situations it is a relevant part of adjuvant therapy). Therefore, this paragraph should be rewritten or deleted, it would be better for the manuscript. Regarding the systematic review itself, I suggest summarizing the main results in the form of tables. One figure demonstrating the role of pro-NGF, NGF, TrkA and NGFR/p75NTR in breast cancer would raise the quality of the work to a higher level.
Author Response
Comment 1. The overview conveys very basic knowledge for laypersons. However, the added value of such a lengthy introduction is questionable as it doesn't really relate to the role of NGF. In particular, paragraph 2.4. "Treatments and prognosis" is an unbalanced and simplified compilation of basic information (e.g. that chemotherapy can cause hair loss; or the information on radiotherapy starts with intraoperative radiotherapy, 3D conformal radiotherapy, does not provide key information that radiotherapy is an integral part of a breast-conserving surgery is and in which situations it is a relevant part of adjuvant therapy). Therefore, this paragraph should be rewritten or deleted, it would be better for the manuscript.
Response 1. Thank you to the reviewer for this feedback. We have now considerably reduced the length of this paragraph, leaving only the information useful for a clear understanding of the second part of the review even for laypersons.
Comment 2. Regarding the systematic review itself, I suggest summarizing the main results in the form of tables.
Response 2. Thank you for this feedback. We have now added a table with an overview of included studies.
Comment 3. One figure demonstrating the role of pro-NGF, NGF, TrkA and NGFR/p75NTR in breast cancer would raise the quality of the work to a higher level.
Response 3. Thank you for this feedback. We have now added a figure demonstrating the role of NGF, TrkA and NGFR/p75NTR in breast cancer. Given the still too preliminary data on pro-NGF, and in line with the request of the other reviewer, we have not added it in the figure.
Round 2
Reviewer 2 Report
The authors did a great job. The manuscript has improved greatly. The added tables and figure improved clarity and quality. I recommend acceptance for publication.