The Relationships Among Perineural Invasion, Tumor–Nerve Interaction and Immunosuppression in Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this study, the author provides a comprehensive review of cancer perineural invasion (PNI) through interactions with Schwann cells in a pan-cancer setting, covering molecular interactions, the role of neural cells in promoting cancer progression, and potential therapeutic strategies. However, two additional aspects might be of interest for further exploration:

1. Do metastatic cancer cells interact with neural cells in a similar manner as primary tumors? Given that metastatic cells have undergone processes such as extravasation and intravasation, often with elevated epithelial-mesenchymal transition (EMT) activity, they may be even more prone to invading neural structures.

2. The review provides limited discussion on the role of PNI in brain or central nervous system (CNS)-related tumors, where neurons are highly abundant in the local microenvironment. A deeper exploration of PNI mechanisms in these contexts could provide important additional insights.

Author Response

Comments and Suggestions for Authors

In this study, the author provides a comprehensive review of cancer perineural invasion (PNI) through interactions with Schwann cells in a pan-cancer setting, covering molecular interactions, the role of neural cells in promoting cancer progression, and potential therapeutic strategies. However, two additional aspects might be of interest for further exploration:

1. Do metastatic cancer cells interact with neural cells in a similar manner as primary tumors? Given that metastatic cells have undergone processes such as extravasation and intravasation, often with elevated epithelial-mesenchymal transition (EMT) activity, they may be even more prone to invading neural structures.

Answer:

Exactly, as the Reviewer suggests: metastatic cells have undergone processes such as extravasation and intravasation, often with elevated epithelial-mesenchymal transition (EMT) activity, they may be even more prone to invading neural structures. The upregulation of relevant pathways result in mechanisms partly similar to neuronal invasion, migration of neural crest-derived cells. Metastatic cancer cells ensure the development of enzymatic functions and invadopodia, which letter includes expression of actin and required structural proteins. Based on related literature we see mechanisms that are shared between neuronal growth and expansion and metastatic tumor cells with sustained EMT activity.

1. WNT signaling and activation of TGF-beta / BMP proteins
2. Invadopodia

Related literature is included now into the manuscript to relevant points. (Page 7, lines 194 - 201).

1. The review provides limited discussion on the role of PNI in brain or central nervous system (CNS)-related tumors, where neurons are highly abundant in the local microenvironment. A deeper exploration of PNI mechanisms in these contexts could provide important additional insights.

Answer:

The reviewer is right, PNI in brain and CNS-tumors would be worth to discuss, moreover, it deserves a whole paper, because of the different background. For central nervous system tumors the invasion is defined as local growth and distant progression. We superficially touch this topic in our review article, just with the aim to facilitate more research in this area. A recent 2024 paper of Bruschi et al. is a good example for the mission taken in this research field. The topic is diffuse midline glioma (DMG) which is a pediatric tumor with  2-year survival after diagnosis. Authors use patient-derived glioma stem cells (GSCs) to create patient-specific 3D avatars to model invasion and elucidate the cellular supporting mechanisms. Authors describe two modes of migration, mesenchymal and ameboid-like, and associate the ameboid-like modality with GSCs derived from the most invasive tumors. They characterize the invasive ameboid-like tumors as oligodendrocyte progenitor-like, with highly contractile cytoskeleton and reduced adhesion ability driven by overexpression of bone morphogenetic pathway 7 (BMP7). These migration mechanisms as the ameboid migration of the PNI and the BMP pathways are described also in relation to invasion of metastatic tumor cells, we feel that integrative knowledge of metastasis invasion research of solid tumors as HNSCC, pancreatic ductal adenocarcinoma and melanoma, and the research of glioma stem cells might generate hypotheses for each other and lead to possibilities for developing therapeutic inhibitors and modulators. To mention and include this point, which can be found now at Page 7; lines 209-224, is a significant improvement of this manuscript, for which we are grateful for the reviewer.

Reviewer 2 Report

Comments and Suggestions for Authors

The review discusses tumor cells within the tumor microenvironment in peripheral nerves. Dedifferentiated Schwann cells trigger partial epithelial to mesenchymal transition, attracting myeloid-derived suppressor cells to activate the TGF-beta signaling pathway. Ultimately, perineural invasion develops. The review fills a gap for an overview of tumor-neural interactions. Very few reviews cover tumor and peripheral nerve interactions, and this review is well-referenced.

 

Minor revision:

1. Lines 252-262, the review discusses the influence of beta-adrenergic receptor activation from sympathetic nerves resulting in tumor metastasis. In addition, the review discusses tumor-associated macrophages as targets for beta-adrenergic receptor signaling. The authors mentioned that tumor-associated macrophages will be discussed later in the article, which they did in the absence of the context of beta-adrenergic receptor signaling. The authors must extend their discussion of the beta-adrenergic receptor signaling effect on tumor-associated macrophages.

Author Response

Comments and Suggestions for Authors

The review discusses tumor cells within the tumor microenvironment in peripheral nerves. Dedifferentiated Schwann cells trigger partial epithelial to mesenchymal transition, attracting myeloid-derived suppressor cells to activate the TGF-beta signaling pathway. Ultimately, perineural invasion develops. The review fills a gap for an overview of tumor-neural interactions. Very few reviews cover tumor and peripheral nerve interactions, and this review is well-referenced.

 Minor revision:

1. Lines 252-262, the review discusses the influence of beta-adrenergic receptor activation from sympathetic nerves resulting in tumor metastasis. In addition, the review discusses tumor-associated macrophages as targets for beta-adrenergic receptor signaling. The authors mentioned that tumor-associated macrophages will be discussed later in the article, which they did in the absence of the context of beta-adrenergic receptor signaling. The authors must extend their discussion of the beta-adrenergic receptor signaling effect on tumor-associated macrophages.

Answer:

The reviewer is right. Tumor-associated macrophages are key targets of β-adrenergic regulation in several cancer contexts, and is a rapidly developing field, with several overlapping findings and literature resources that confirm each other. The related papers discuss mainly stress, where epinephrine for example facilitate the switch to M2 macrophages. These data confirm the effects of physiological stress on the immune system, and mechanistically underline the immune suppressive role of stress. This point is extended by a citation of a paper about propranolol, a nonselective beta-blocker, which could have been used for the treatment of metastatic angiosarcoma. The effects included reduction of myeloid-derived suppressor cells, increase of T cell infiltration and reduction of tumor angiogenesis. Moreover, PD-L1 was upregulated on tumor associated macrophages. A further study using a sleep-deprived tumor-bearing mouse model evidenced that in non-small cell lung cancer (NSCLC) that sleep deprivation leads to upregulation of beta2-adrenergic receptor (ADRB2), and facilitates the pro-tumoral M2 macrophages polarization. These points are now included in page 9, lines 311-324.

Reviewer 3 Report

Comments and Suggestions for Authors

This paper provides a comprehensive summary of the relationship between tumor growth and nerve innervation, with particular emphasis on the role of Schwann cells. The review incorporates extensive and up-to-date data from well-established studies and highlights informative findings, especially regarding the high Schwann cell profile in head and neck squamous cell carcinoma (HNSCC).

Comment

• Section 3, Nerves and Cancer: This section includes excessive data from each cited reference, making it somewhat redundant. In particular, phrases such as “Schwann cells migrate to the nests of cancer cells” and “the immunosuppressive effect of TGF-β” are repeated multiple times. It would be clearer and more effective to organize this section under several subheadings, such as “from the perspective of innervation,” “from the tumor side,” and “from the tumor microenvironment,” and discuss each aspect separately.

Comments on the Quality of English Language

OK

Author Response

Comments and Suggestions for Authors

This paper provides a comprehensive summary of the relationship between tumor growth and nerve innervation, with particular emphasis on the role of Schwann cells. The review incorporates extensive and up-to-date data from well-established studies and highlights informative findings, especially regarding the high Schwann cell profile in head and neck squamous cell carcinoma (HNSCC).

Comment

• Section 3, Nerves and Cancer: This section includes excessive data from each cited reference, making it somewhat redundant. In particular, phrases such as “Schwann cells migrate to the nests of cancer cells” and “the immunosuppressive effect of TGF-β” are repeated multiple times. It would be clearer and more effective to organize this section under several subheadings, such as “from the perspective of innervation,” “from the tumor side,” and “from the tumor microenvironment,” and discuss each aspect separately.

Answer:

Authors are grateful for these constructive suggestions, which were followed by the revision. Revised, rephrased and redistributed text components are labelled in red. See Page 5 line 125 – Page 10 line 348.