The Metastatic Capacity of Melanoma Reveals Alternative Pathways of Cancer Dissemination
Round 1
Reviewer 1 Report
The manuscript entitled “Alternative Pathway for Cancer Metastasization” addresses alternative tumor behaviors by angiogenic and vasculogenic processes and describes modalities of metastasization. The article also summarizes the available models for the evaluation of angiotropism or EVMM of melanoma cell lines.
1. This is a review article by description of cancer metastasization. It is better if authors can use a figure to illustrate the metastatic mechanism and a table to compare the different metastatic processes. It will let article to be more comprehensive and help readers to understand quickly.
2. The article mainly discuss melanoma, which does not completely match the title of this article.
3. In the text, "4. The angiotropic process: walking on the abluminal side of vessel. Recently, pathologists described the presence of single cancer cells or cell aggregates near vessels on the outer side in melanoma samples (Table 1)". The description of these words cannot explain the phenomena in different types of cancer cells in Table 1.
4. In the text, "6. Approaches to study angiotropism and EVMM". The available models for the evaluation of angiotropism or EVMM of melanoma cell lines should describe its advantages, disadvantages and limitations that help readers quickly to understand
5. There are many repeat abbreviations and definitions in the text, which may be considered as key words.
Author Response
Editor International Journal of Translational Medicine
Many thanks for your previous correspondence on our manuscript entitled “Alternative Pathway for Cancer Metastasization” (ijtm-1350609). We thank the Reviewers for having provided inputs to improve our manuscript. We have read carefully and addressed all the Reviewer’s comments. Please find enclosed our revised manuscript and a point-by-point response to the Reviewers’ comments below (our response in italics).
Reviewer #1:
The manuscript entitled “Alternative Pathway for Cancer Metastasization” addresses alternative tumor behaviors by angiogenic and vasculogenic processes and describes modalities of metastasization. The article also summarizes the available models for the evaluation of angiotropism or EVMM of melanoma cell lines.
- This is a review article by description of cancer metastasization. It is better if authors can use a figure to illustrate the metastatic mechanism and a table to compare the different metastatic processes. It will let article to be more comprehensive and help readers to understand quickly.
Following the reviewer’s suggestion, we have included in the revised version a schematic cartoon (see section 4) of the possible cancer dissemination routes; Table 1 associated to the Figure 1 summarizes the specific features of the different routes.
- The article mainly discuss melanoma, which does not completely match the title of this article.
According to reviewer’s suggestion, we have changed the old title “Alternative Pathway for Cancer Metastasization” into “The metastatic capacity of melanoma reveals alternative pathways of cancer dissemination”.
- In the text, "4. The angiotropic process: walking on the abluminal side of vessel. Recently, pathologists described the presence of single cancer cells or cell aggregates near vessels on the outer side in melanoma samples (Table 1)". The description of these words cannot explain the phenomena in different types of cancer cells in Table 1.
We agree with the reviewer’s statements and we apologize for the non-clarity of Table 1’s description. In our revised manuscript, we modified the description of the table 1 (now table 2) to make it clearer and better match its content (see section 4).
- In the text, "6. Approaches to study angiotropism and EVMM". The available models for the evaluation of angiotropism or EVMM of melanoma cell lines should describe its advantages, disadvantages and limitations that help readers quickly to understand
We thank the reviewer for her/his comment. According to the reviewer suggestions we implemented section 6 of the revised version with advantages and limitations of the methods described (see section 6 of the main text).
5. There are many repeat abbreviations and definitions in the text, which may be considered as key words.
According to reviewer’s suggestion, we added some key words to the main text.
Author Response File: 
Author Response.docx
Reviewer 2 Report
In the manuscript entitled "Alternative Pathway for Cancer Metastasization" with Manuscript ID ijtm-1350609 by Michela Corsini, Cosetta Ravelli , Elisabetta Grillo , Stefania Mitola, the authors review molecular mechanisms and morphofunctional modifications leading to alternative modalities of tumor metastization (different strategies that tumors can adopt to grow and dissemination). The work is interesant and well written. I only have minor considerations.
In section 4, It is convenient to differentiate between tumor cells (melanoma cells) along the abluminal vascular surface toward secondary sites (hypothesis of Lugassy C. et al.), in which the term pericytic mimicry emphasizes the replacement of pericytes by neoplastic cells and the concept of Cheng L. et al., in which glioblastoma stem cells generate vascular pericytes.
When exposing the intussusceptive microvascular growth in section 2, it could be briefly extended to its counterpart intussusceptive lymphangiogenesis.
Author Response
Editor International Journal of Translational Medicine
Many thanks for your previous correspondence on our manuscript entitled “Alternative Pathway for Cancer Metastasization” (ijtm-1350609). We thank the Reviewers for having provided inputs to improve our manuscript. We have read carefully and addressed all the Reviewer’s comments. Please find enclosed our revised manuscript and a point-by-point response to the Reviewers’ comments below (our response in italics).
Reviewer #1:
The manuscript entitled “Alternative Pathway for Cancer Metastasization” addresses alternative tumor behaviors by angiogenic and vasculogenic processes and describes modalities of metastasization. The article also summarizes the available models for the evaluation of angiotropism or EVMM of melanoma cell lines.
- This is a review article by description of cancer metastasization. It is better if authors can use a figure to illustrate the metastatic mechanism and a table to compare the different metastatic processes. It will let article to be more comprehensive and help readers to understand quickly.
Following the reviewer’s suggestion, we have included in the revised version a schematic cartoon (see section 4) of the possible cancer dissemination routes; Table 1 associated to the Figure 1 summarizes the specific features of the different routes.
- The article mainly discuss melanoma, which does not completely match the title of this article.
According to reviewer’s suggestion, we have changed the old title “Alternative Pathway for Cancer Metastasization” into “The metastatic capacity of melanoma reveals alternative pathways of cancer dissemination”.
- In the text, "4. The angiotropic process: walking on the abluminal side of vessel. Recently, pathologists described the presence of single cancer cells or cell aggregates near vessels on the outer side in melanoma samples (Table 1)". The description of these words cannot explain the phenomena in different types of cancer cells in Table 1.
We agree with the reviewer’s statements and we apologize for the non-clarity of Table 1’s description. In our revised manuscript, we modified the description of the table 1 (now table 2) to make it clearer and better match its content (see section 4).
- In the text, "6. Approaches to study angiotropism and EVMM". The available models for the evaluation of angiotropism or EVMM of melanoma cell lines should describe its advantages, disadvantages and limitations that help readers quickly to understand
We thank the reviewer for her/his comment. According to the reviewer suggestions we implemented section 6 of the revised version with advantages and limitations of the methods described (see section 6 of the main text).
- There are many repeat abbreviations and definitions in the text, which may be considered as key words.
According to reviewer’s suggestion, we added some key words to the main text.
Reviewer #2:
In the manuscript entitled "Alternative Pathway for Cancer Metastasization" with Manuscript ID ijtm-1350609 by Michela Corsini, Cosetta Ravelli, Elisabetta Grillo, and Stefania Mitola, the authors review molecular mechanisms and morphofunctional modifications leading to alternative modalities of tumor metastization (different strategies that tumors can adopt to grow and dissemination). The work is interesant and well written. I only have minor considerations.
In section 4, it is convenient to differentiate between tumor cells (melanoma cells) along the abluminal vascular surface toward secondary sites (hypothesis of Lugassy C. et al.), in which the term pericytic mimicry emphasizes the replacement of pericytes by neoplastic cells and the concept of Cheng L. et al., in which glioblastoma stem cells generate vascular pericytes.
According to reviewer’s suggestion, we have discuss the pericyte mimicry in melanoma and glioblastoma in section 4
When exposing the intussusceptive microvascular growth in section 2, it could be briefly extended to its counterpart intussusceptive lymphangiogenesis.
According to reviewer’s suggestion, we have introduced the intussusceptive lymphangiogenesis
Sincerely,
Prof. Stefania Mitola
Author Response File: Author Response.docx
Round 2
Reviewer 1 Report
The manuscript entitled “Alternative Pathway for Cancer Metastasization” changed into “The metastatic capacity of melanoma reveals alternative pathways of cancer dissemination” that had been improved after revise.
Minor criticisms:
The paragraph “The mouse model represents the “top-level model” in preclinical cancer research. Indeed mouse present several advantages including the high conservation with humans in term of anatomy, physiology and genetics which help to better model the metastatic process. Moreover, it provides a good tool for drug discovery and verification. The variety of mouse strains, including humanized mice, opened to many cancer cell lines and PDX research. However, obtaining and maintaining the animals can be very expensive and require highly specialized personnel＂lack citation.
Author Response
We thank the reviewer for his/her additional comment. In the revised version we added some references to the paragraph of murine models.
Sincerely Stefania Mitola
Author Response File: Author Response.docx
