How Schwann Cells Are Involved in Brain Metastasis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Authors present a review article on role of Schwann cells in mechanisms of brain metastases. Authors do not define this review as a systematic, scoping or narrative review; they do not present methodology which led to the inclusion of certain papers in this review. I suggest to include a PRISMA flow chart and define the criteria; otherwise, this is a mere book chapter or experts opinion. Authors do not provide any clinical aspects, possible target mechanisms or consequences of their review.

Author Response

Thank you for your suggestions. This is indeed a narrative review so a PRISMA flow chart would not be appropriate, however, we are happy to include some text about selection criteria which has been added to the introduction.

Please see line 66-71 or the following text. “This narrative review focuses on the relatively new field of SC metastasis research. Case reports of brain metastasis from primary cancers have been pooled along with animal and in vitro models of brain metastasis and SC interference. Some examples of search criteria included, “brain metastasis and SCs”, “SCs metastasis”, “SC perineural invasion”, and “SCs and (specific type of primary cancer)”.”

 

In regard to the lack of clinical aspects, Schwann cell research as it relates to cancer metastasis is a relatively new field and there is a lack of clinical information, and diagnostic criteria, on the subject. We appreciate that consequences of this review might be lacking in the conclusion section and have added additional text to account for this.

Please see line 340-344 or the following text. “The information in this review shows the lack of clinical diagnosis of SC identification in brain metastasis and discusses research specific to primary cancers that could shed light on the mechanisms for metastasis from each of these cancer types. With this information, future research can focus on these mechanisms to potentially target treatments for patients with high risk for SC involved brain metastasis.”

Reviewer 2 Report

Comments and Suggestions for Authors

The review paper entitled „Schwann cells Involvement in Brain Metastasis” is generally well written, interesting and easy to follow.

However, in order to make this manuscript better I have some remarks and suggestions:

Is the title of the paragraph: “Schwann cells roll in metastasis” a clerical error?

In general, the manuscript needs some serious read-through and check for editorial errors.

When discussing processes of secretion of chemotactic factors, and response of SCs to stimulation by cancer cell it would be beneficial for the readers to explain what receptors are expressed by SCs and which play key roles in processes of metastasis.

In Line 98 “Removing this ECM can prevent the onset of metastasis [24]” there is some oversimplification of the cited research and some more data on “induce a prometastatic phenotype” is needed.

In Line 134-135, except for another clerical error in “secretion”, it is hard understand what the authors mean by “…progression of certain lung cancers…” what are these “certain lung cancers”?

In “Melanoma” paragraph the authors write about “tumor innervation”, in my opinion it would be very interesting to create separate paragraph in the introduction section on this phenomenon and its relation to SCs aided metastasis.

Comments on the Quality of English Language

In general, the manuscript needs some serious read-through and check for editorial errors.

Author Response

The review paper entitled „Schwann cells Involvement in Brain Metastasis” is generally well written, interesting and easy to follow.

However, in order to make this manuscript better I have some remarks and suggestions:

Is the title of the paragraph: “Schwann cells roll in metastasis” a clerical error?

Thank you for pointing out this error. We have adjusted the name for clarity and to correct the error.

In general, the manuscript needs some serious read-through and check for editorial errors.

We have read through the manuscript and checked for these errors.

When discussing processes of secretion of chemotactic factors, and response of SCs to stimulation by cancer cell it would be beneficial for the readers to explain what receptors are expressed by SCs and which play key roles in processes of metastasis.

Text discussing SC receptors has been added. Please see line 81-87 or the following text. “Several receptors expressed by SCs are necessary for the interaction and activation by cancer cells. For example, CXCR4 is expressed by SCs and is necessary for their re-cruitment and activation by CXCL12 [19]. SCs also express p75NTR which is a low affinity receptor for nerve growth factor that also activated migration of both SCs and cancer cells [11]. Tumor activated SCs are also known to highly expressed GFAP and other pre-myelinating genes such as NCAM and L1-CAM which are necessary for nerve repair functions and metastatic functions [16,17].”

In Line 98 “Removing this ECM can prevent the onset of metastasis [24]” there is some oversimplification of the cited research and some more data on “induce a prometastatic phenotype” is needed.

We appreciate the feedback and have adjusted the text for clarity. Please see line 138-144 or the following text. “For instance, increased dietary intake of palmitic acid induces a pro-metastatic state in oral and melanoma cancer cells, which has been linked to increased activation of SCs and greater tumoral innervation. [24] Activated SCs from these experiments were able to secrete proregenerative extracellular matrix (ECM). [24] When this ECM is ablated, the initiation of metastasis by cancer cells in inhibited. [24] These changes are induced by the transcription factor EGR2 in cancer cells and the peptide galanin. [24]”

In Line 134-135, except for another clerical error in “secretion”, it is hard understand what the authors mean by “…progression of certain lung cancers…” what are these “certain lung cancers”?

Clarification on the specific lung cancers has been included. Please see line 176 or the following text. “The secretion of paracrine signals or EVs can also accelerate the progression of certain lung cancers, such as lung adenocarcinoma and lung squamous cell carcinoma.[25, 31]”

In “Melanoma” paragraph the authors write about “tumor innervation”, in my opinion it would be very interesting to create separate paragraph in the introduction section on this phenomenon and its relation to SCs aided metastasis.

We agree that this is an interesting phenomenon and have added a brief discussion of this topic in the introduction. Please see line 38-45 or the following text. “Tumor innervation from the PNS is strongly correlated with poor prognosis because it is associated with aggressive tumor phenotypes and has been implicated in tumor me-tastasis by way of locally delivered neurotransmitters [6,7]. Recently, however, it has been found that extracellular vesicles (EVs) can also induce tumor innervation by way of the release of axon guidance and neurotrophic factors [8]. The connection between tumor innervation and Schwann cells (SCs) is less well understood, but EVs have also been found to activate SCs to induce metastases through mechanisms discussed later in this review.”

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Sufficient response by authors.