Interrupting Neuron—Tumor Interactions to Overcome Treatment Resistance

Round 1

Reviewer 1 Report

It is well written, the flow is very logic, easy to ready and very fascinating. I don't have specific comments. It undoubetly warrants direct publication in Cancers and thereby I have no hesitation to support its acceptance.

Author Response

It is well written, the flow is very logic, easy to ready and very fascinating. I don't have specific comments. It undoubtedly warrants direct publication in Cancers and thereby I have no hesitation to support its acceptance.

Thank you for your support and positive feedback.

Reviewer 2 Report

Strengths:

In this review article, the authors have provided an interesting, extensive and detailed review of an emerging area indicating how interrupting neuro-tumor interactions overcome treatment resistance in tumors. More so, they have thoroughly discussed how interactions between neurons and tumors modulate TME to provide a safety zone for the tumors to escape drug-induced tumor destruction while such interactions enhance the neuronal growth and tumor progression and survival. The article described this symbiotic-type of relationship between neurons and tumors. Their review article also discusses potential roles of cAMP-PKA-dependent signaling triggered in neurons by cathecholamines with consequences in enhanced tumor growth and promotion of TME, which in turn enhanced neurogenesis. Furthermore, the authors discussed the effects and mechanisms of several blockers of cAMP-PKA inhibitors currently under phase 1 clinical trials for their potential anti-tumor effects in different types of cancer. They also discussed other major signaling pathways including PI-3K/Akt and MAPK in mediating the interplay between neurons and tumors to generate tumor resistance and tumor progression. They also discussed potential roles of different miRNAs carried by exosomes and play different roles in this interplay between neurons and tumors. Lastly, the authors discussed how evaluation of some oncothropic and growth factors that play key roles in neuron-tumor interaction as tumor markers, can be very useful in both cancer patient diagnosis and patient prognosis.     

Overall, this is a well-written review that will  enrich our knowledge in this new and rapidly emerging area which could become vital for future development of new therapies and/or adjuvant therapies to abrogate the otherwise strong neuron-tumor resistance that contribute to tumorigenesis and tumor resistance. The article cites extensive references to support the article. The articles will provide extensive knowledge to the field and will be attractive to readers in the field of neuro-oncology as well as scientist outside this field.

Concerns/Suggestions:

• Much as the authors provided extensive citations in support of the article, the article could even become much interesting by inclusion of some citations omitted by the authors in this review.

1. The authors extensively discussed the role by PKA in the neuron-tumor interactions. However, given that PKA has multiple downstream target proteins, it would be important to expand this section by mentioning specific PKA-target protein that has been implicated in this interaction and for which a new cancer therapy can be developed to disrupt the interaction. Below citations should be considered.

• Targeting cAMP signaling in hepatocellular carcinoma by Mara Massimi et al (2019) in Cells 8(12); 1511
• Targeting PKA in cancer therapy: an update on roles of CREB by Luigi Sapio et al (2014) EXCLI. Journal

• On lines 125 and 126, the authors eluded to the potential role of STAT3 signaling triggered by cathecholamines in promoting the neuron-tumor interactions, but they did not go any further. Notably, they did not discuss which Jak kinases may be involved in activating STAT3 and also whether other STAT proteins are involved. There are several strong inhibitors of specific Jak kinases and may have been studied. Secondly, there are STAT3 inhibitors that have shown promise as new therapeutic lead and can be combined with other chemotherapies to improve patient outcomes. Therefore, inclusion of few articles that support these anti-tumor effects via inhibition of Jak kinases and/or STAT3 can expanded in this review article to enhance the pool of readers.
• The authors nicely described the role of glucagon-induced glucose metabolism in supporting these neuron-tumor interactions that promoted both neurogenesis and tumor growth. This is critical under fasting state in tumors. However, under fed state insulin released in response to elevated blood glucose can trigger insulin-receptor signaling that can promote the neuron-tumor interaction to the benefit of the tumor survival and resistance to specific therapies. This aspect should also be considered. Below are couple of citations that the authors could consider.
• Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation by Yuanying Gong et al (2015 online and January 2016 in Neuro Oncol. 18 (1) 48-57.
• Insulin signaling mediates neurodegeneration in glioma by Patricia Jarabo et al.

Author Response

In this review article, the authors have provided an interesting, extensive and detailed review of an emerging area indicating how interrupting neuro-tumor interactions overcome treatment resistance in tumors. More so, they have thoroughly discussed how interactions between neurons and tumors modulate TME to provide a safety zone for the tumors to escape drug-induced tumor destruction while such interactions enhance the neuronal growth and tumor progression and survival. The article described this symbiotic-type of relationship between neurons and tumors. Their review article also discusses potential roles of cAMP-PKA-dependent signaling triggered in neurons by cathecholamines with consequences in enhanced tumor growth and promotion of TME, which in turn enhanced neurogenesis. Furthermore, the authors discussed the effects and mechanisms of several blockers of cAMP-PKA inhibitors currently under phase 1 clinical trials for their potential anti-tumor effects in different types of cancer. They also discussed other major signaling pathways including PI-3K/Akt and MAPK in mediating the interplay between neurons and tumors to generate tumor resistance and tumor progression. They also discussed potential roles of different miRNAs carried by exosomes and play different roles in this interplay between neurons and tumors. Lastly, the authors discussed how evaluation of some oncothropic and growth factors that play key roles in neuron-tumor interaction as tumor markers, can be very useful in both cancer patient diagnosis and patient prognosis.    

Overall, this is a well-written review that will enrich our knowledge in this new and rapidly emerging area which could become vital for future development of new therapies and/or adjuvant therapies to abrogate the otherwise strong neuron-tumor resistance that contribute to tumorigenesis and tumor resistance. The article cites extensive references to support the article. The articles will provide extensive knowledge to the field and will be attractive to readers in the field of neuro-oncology as well as scientist outside this field. 

Much as the authors provided extensive citations in support of the article, the article could even become much interesting by inclusion of some citations omitted by the authors in this review. 

1. The authors extensively discussed the role by PKA in the neuron-tumor interactions. However, given that PKA has multiple downstream target proteins, it would be important to expand this section by mentioning specific PKA-target protein that has been implicated in this interaction and for which a new cancer therapy can be developed to disrupt the interaction. Below citations should be considered:

Targeting cAMP signaling in hepatocellular carcinoma by Mara Massimi et al (2019) in Cells 8(12); 1511

Targeting PKA in cancer therapy: an update on roles of CREB by Luigi Sapio et al (2014) EXCLI. Journal

We agree with the reviewer and have included the recommended citation by Massimi et al., the recommended citation by Sapio et al., as well as a review by Bucko and Scott. We have added the following sentences to further expand on how targeting the A kinase-anchoring proteins (AKAPs) and cyclic AMP may be therapeutic avenues for disrupting neuron-tumor interactions (lines 294-303): “PKA regulates a vast number of downstream substrates and processes. In addition to leveraging PKA activity as a biomarker of disease, proteins involved in PKA function and localization can be used as metrics of disease presence and progression. The regulatory subunits of PKA bind with high affinity to a variety of scaffolding proteins called A kinase anchoring proteins (AKAPs) which localize these PKA subunits to the vicinity of their physiological substrates. These PKA-AKAP interactions have been shown to be important in cancer, and anti-cancer therapies that disrupt these interactions are currently being developed [92,93]. Cyclic AMP activates PKA and is known to be misregulated in ovarian, pancreatic, lung, and hepatocellular cancers. Efforts to measure and manipulate cAMP levels are an additional developing area of therapeutic promise [94]. Further work is needed to determine the role that these interactions play in mediating neuron-tumor relationships.”     

2. On lines 125 and 126, the authors eluded to the potential role of STAT3 signaling triggered by cathecholamines in promoting the neuron-tumor interactions, but they did not go any further. Notably, they did not discuss which Jak kinases may be involved in activating STAT3 and also whether other STAT proteins are involved. There are several strong inhibitors of specific Jak kinases and may have been studied. Secondly, there are STAT3 inhibitors that have shown promise as new therapeutic lead and can be combined with other chemotherapies to improve patient outcomes. Therefore, inclusion of few articles that support these anti-tumor effects via inhibition of Jak kinases and/or STAT3 can expanded in this review article to enhance the pool of readers.

We appreciate this recommendation and have added the following sentences to elaborate on the pro-tumorigenic/anti-tumor effects of activation/inhibition of STAT3 and included a citation for a comprehensive review of IL-6/JAK/STAT3 signaling in cancer (lines 134-141): “Importantly, this study demonstrated that blocking STAT3 in vitro inhibited norepinephrine-induced pancreatic cancer cell migration, invasion, and PNI, and that treatment with a STAT3 phosphorylation inhibitor blocked PNI of pancreatic cancer cells in vivo. Additional studies have shown similar pro-tumorigenic alterations of the TME by STAT3 activation and notable antitumor effects of STAT3 inhibition in a variety of cancers (for a comprehensive review on IL-6/JAK/STAT3 signaling in cancer, see Johnson et al. [39]). These data suggest that STAT3 signaling warrants further investigation as a mediator of the interaction between sympathetic nerves and cancer cells.”

3. The authors nicely described the role of glucagon-induced glucose metabolism in supporting these neuron-tumor interactions that promoted both neurogenesis and tumor growth. This is critical under fasting state in tumors. However, under fed state insulin released in response to elevated blood glucose can trigger insulin-receptor signaling that can promote the neuron-tumor interaction to the benefit of the tumor survival and resistance to specific therapies. This aspect should also be considered. Below are couple of citations that the authors could consider: 

Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation by Yuanying Gong et al (2015 online and January 2016 in Neuro Oncol. 18 (1) 48-57.

Insulin signaling mediates neurodegeneration in glioma by Patricia Jarabo et al.

 We greatly appreciate this suggestion and agree that the role that insulin signaling plays in tumorigenesis is an important topic to include in our discussion. To address the possibility of insulin signaling mediating neuron-tumor interactions, we have added the following sentences to our manuscript (lines 312–315): “Interestingly, insulin misregulation has been linked to tumorigenesis and chemoresistance [97,98]. Additionally, insulin signaling acts on neurons of the peripheral and central nervous systems [99,100]. Whether the observed increase in tumor growth and treatment-resistance is mediated by neuron-tumor interactions requires further investigation.”

Reviewer 3 Report

The review article "Interrupting Neuron-Tumor Interactions to
Overcome Treatment Resistance" is a comprehensively written manuscript describing the relationship between neurons and cancer cells in cancer progression and the therapeutic importance of targeting Neuron-Tumor Interactions. The review article should also add a section on "tumor/cancer-cell acting as neuron" in the article, which is missing here, along with the complexities and therapeutic importance. Please describe how metastatic cancer cells make synapse and act as a neuron to potentiate its growth. Please mention/cite the source of Figure 2.

Author Response

The review article "Interrupting Neuron-Tumor Interactions to Overcome Treatment Resistance" is a comprehensively written manuscript describing the relationship between neurons and cancer cells in cancer progression and the therapeutic importance of targeting Neuron-Tumor Interactions. The review article should also add a section on "tumor/cancer-cell acting as neuron" in the article, which is missing here, along with the complexities and therapeutic importance. Please describe how metastatic cancer cells make synapse and act as a neuron to potentiate its growth. Please mention/cite the source of Figure 2.

We thank you very much for your positive feedback and your suggestions on how to improve our review. In this work we clearly and thoroughly discuss how cancer cells act as neurons in their ability and predilection to release neurotransmitters and neurotrophic factors. However, to further describe the ability of cancer cells to form synapses to promote their own growth, we have added the following sentences (lines 98-102): “To maximize their access to these neuronally released signals, cancer cells form tripartite synapses with pre-synaptic and post-synaptic terminals of nearby neurons [26]. These tumor cells concomitantly express neurotransmitter receptors, including NMDAR, which when activated, drive neuron-tumor trophic interactions [27–29].”

The data presented in Figure 2 are original to this manuscript. We signified this using the language “MiR-324 is a potent neuritogenic signal, which we have found to be profoundly upregulated in densely innervated oral tumors when compared to poorly innervated oral tumors (Figure 2).” However, to further clarify that these data are original to this manuscript, we have added the phrase “Data are original to this manuscript” to the Figure 2 legend (lines 246-247).