A Systematic Role of Metabolomics, Metabolic Pathways, and Chemical Metabolism in Lung Cancer

Round 1

Reviewer 1 Report

The review article (vaccines-2183051) written by Sandra K et al., summarizes the development of metabolism and metabolic pathways in lung cancer (LCa). The review manuscript was very exciting to be read and presents interesting about metabolomics in lung cancer metabolisms.

This manuscript shape and outline can be interesting but the Authors should explain in more points about LCa metabolomics. The manuscript possesses novelty and therefore it has potential to interest the readers from LCa. I affirm its acceptance for publication in metabolites with miner revision. However, the following comments must be answered by the authors prior to publication. 

1. Title could revise with metabolomics. Author should revise the title “A systematic role of metabolomics, metabolic pathways, and chemical metabolism in lung cancer”.   

2. Add few more keywords in manuscript.

3. LCa is not suitable abbreviation in manuscript. Use LC in full manuscript. 

4. Revise the abstract with LC abbreviation.  

5. In conclusion part, explain about the future changes of LC. Conclusions should be developed.

6. Most of the paragraph are too length to read and understand. Author should split it.

Author Response

Reviewer 1:

We are very much thankful to the reviewer for reviewing this manuscript and providing such valuable comments to improve the quality of the manuscript. We have again carefully revised the entire manuscript and have tried to address all the issues very carefully.

The review article (vaccines-2183051) written by Sandra K et al., summarizes the development of metabolism and metabolic pathways in lung cancer (LCa). The review manuscript was very exciting to be read and presents interesting about metabolomics in lung cancer metabolisms.

This manuscript shape and outline can be interesting but the Authors should explain in more points about LCa metabolomics. The manuscript possesses novelty and therefore it has potential to interest the readers from LCa. I affirm its acceptance for publication in metabolites with miner revision. However, the following comments must be answered by the authors prior to publication. 

1. Title could revise with metabolomics. Author should revise the title “A systematic role of metabolomics, metabolic pathways, and chemical metabolism in lung cancer”.   

Response: The title has been changed to “A systematic role of metabolomics, metabolic pathways, and chemical metabolism in lung cancer”

2. Add few more keywords in manuscript.

Response: Three key words have been added: Glycolysis, Amino acids, Lipids

3. LCa is not suitable abbreviation in manuscript. Use LC in full manuscript. 

Response: LCa has been changed to LC

4. Revise the abstract with LC abbreviation.  

Response: Abstract has been revised with LC abbreviation

5. In conclusion part, explain about the future changes of LC. Conclusions should be developed.

Response: Conclusion has been modified with future changes. Please find the added information below.

Observing the metabolic alterations in biofluids before, during, and after chemotherapy, could be beneficial for detecting tumour growth. Understanding of intermediates that alter uniquely in distinct types of lung tumours may not only help with clinical diagnosis, but may also identify relevant molecular targets for the design of novel anticancer treatments, thereby improving overall patient survival. Despite the identification of about 150 metabolites or more that are linked to lung cancer, there continues to be more variation due to a lack of standardised patient cohorts and testing techniques.

6. Most of the paragraph are too length to read and understand. Author should split it.

Response: The paragraphs are split according to the information added.

 

 

Reviewer 2 Report

In this present review authors have focused to give the  metabolic pathway changes associated with lung cancer . 

 

Authors have tried to cover the major metbaolic pathway changes associated with cancer. 

 

1 . Authors may have discuss little more studies performed using other technique like NMR metabolomics .

 

2. In BALF (line 146-206) section authors have discuused the importance of balf for the metabolomics studies. Author may also include the metabolomics research have been done using balf sample that will increase the importance of balf sample use.

3. Line 143  (Car-143 rola et al., performed nuclear magnetic resonance (NMR)-based metabolomics in blood 144 plasma and urine for studying the metabolomic patterns in LCa ) lacs the proper references.

4 Author may also give little information about the studies using pathway interpretation methods using metabolic changes.

Author Response

Reviewer 2:

We are very much thankful to the reviewer for reviewing this manuscript and providing such valuable comments to improve the quality of the manuscript. We have again carefully revised the entire manuscript and have tried to address all the issues very carefully.

In this present review authors have focused to give the metabolic pathway changes associated with lung cancer. 

Authors have tried to cover the major metabolic pathway changes associated with cancer. 

1. Authors may have discussed little more studies performed using other technique like NMR metabolomics.

Response: A small paragraph on NMR metabolomics and the studies done are added under the section 8. Please find the added information below.  

“Metabolite analysis of blood plasma using 1H-NMR spectroscopy holds significant promise for early cancer detection and understanding metabolic abnormalities in cancer. Furthermore, because it only takes a few minutes to produce a spectrum, 1H-NMR is well suited for high-throughput screening [167]. However, NMR has shortcomings, the most significant of which are its inherent poor sensitivity and signal overlap. 1H-NMR-based metabolomics developed resulted in an OPLS-DA model that correctly classified 78% of lung cancer patients and 92% of controls. Another study using NMR metabolomics indicated that the following metabolite biomarkers, isoleucine, acetoacetate, and creatine, along with the two NMR signals of N-acetylated glycoproteins and glycerol, might possibly be effective in identifying lung cancer stages [169].”

2. In BALF (line 146-206) section authors have discussed the importance of BALF for the metabolomics studies. Author may also include the metabolomics research have been done using balf sample that will increase the importance of balf sample use.

Response: In section 4, more information regarding the significance of BALF have been added. Studies were BALF is used have also been included. Section 3.2 also discusses about the studies using BALF.

“Beyond cytology, few research have looked at the significance of BALF in detecting lung cancer. BALF cfDNA may be used as a liquid biopsy medium that helped in discriminating small malignant tumours from benign tumours [68]. Another study using BALF found that TIMP-1, Lipocalin-2, and Cystatin-C plasma levels were observed to be considerably higher in adenocarcinomas and squamous cell carcinomas when compared to controls [69].”

3. Line 143 (Car-143 rola et al., performed nuclear magnetic resonance (NMR)-based metabolomics in blood 144 plasma and urine for studying the metabolomic patterns in LCa) lacs the proper references.

Response: This sentence has been removed and added to section 8 for better explanation of NMR techniques.

4. Author may also give little information about the studies using pathway interpretation methods using metabolic changes.

Response: Under section 9, a paragraph on how pathway analysis methods and strategies will aid in the LC diagnosis and therapeutics is discusses with references. Please find the information added below.  

“The pathways implicated in lung cancer prognosis are largely engaged in metabolism, such as tyrosine metabolism and DNA replication process. Meanwhile, cancer-related signalling is mediated by diagnosis-related pathways such as the MAPK signalling system and the GnRH signalling circuit [172]. This suggest that the markers for LC diagnosis and prognosis appeared completely different. Therefore, understanding the difference between them using pathway analysis is important. “

 

Reviewer 3 Report

·         Abstract: The aim of the review should be clearly mentioned. There is also need to define the criteria adopted to perform the search strategy (e.g. Pubmed/Medline, Web of Science…etc).

·         Some studies related to the topic are missing (Int J Biol Markers. 2022 Nov 14;3936155221137359; Front Pharmacol. 2022 Aug 11;13:949745; Metabol Open. 2021 Dec; 12: 100127; J Transl Med. 2020 Jun 17;18(1):243; RSC Adv. 2019 Apr 8;9(19):10905-10913).

·         The introduction is very short and devoted of recent literature to the topic. In Line 39-42, authors should clarify that “lung cancer is divided into two broad histologic classes: small-cell lung carcinomas (SCLC) and non-small lung cancer (NSCLC). NSCLC is further classified into three phenotypes, including adenocarcinoma...etc. There is also need to explore the therapeutic strategies in LC. Much progress have been achieved during last decade including combination treatments with chemo+ IO and targeted therapies for mutated patients like EGFR/ALK/ROS1/KRAS pts. Please put more focus on the progress during last years, and despite that to mention that the prognosis still dismal. Also, smoking increases lung cancer but not all types of lung cancer. For example, some lung cancer patients harboring EGFR mutations do not smoke (Please refer to Healthcare (Basel). 2022 Dec; 10(12): 2501). The novelty of this paper is very weak. There are some reviews/systematic reviews of its kinds (Metabolites. 2021 Sep; 11(9): 630; Int J Mol Sci. 2022 May 17;23(10):5602). How this review extends reader understanding of the topic. What is new? What this review adds? This should be clearly explored at the end of the section.

·         The method section is missing. Authors reviewed several studies but it is not clear how these studies were chosen for inclusion in the review. The section should include search terms, databases, years conducted, study type (vivo/vitro), inclusion/exclusion criteria…etc.

·     There is need to include an additional section about metabolomic-based biomarkers for lung cancer smokers and nonsmokers. There are several studies discussed this point.

·         Please do not include references in the conclusion.

Author Response

Reviewer 3:

We are very much thankful to the reviewer for reviewing this manuscript and providing such valuable comments to improve the quality of the manuscript. We have again carefully revised the entire manuscript and have tried to address all the issues very carefully.

1. Abstract: The aim of the review should be clearly mentioned.

 

Response: The aim of the study has been added to the abstract.

 

2. There is also need to define the criteria adopted to perform the search strategy (e.g., PubMed/Medline, Web of Science…etc).

 

3. Some studies related to the topic are missing (Int J Biol Markers. 2022 Nov 14;3936155221137359; Front Pharmacol. 2022 Aug 11; 13:949745; Metabol Open.2021 Dec; 12: 100127; J Transl Med. 2020 Jun 17;18(1):243; RSC Adv. 2019 Apr 8;9(19):10905-10913).

 

Responses: The above-mentioned studies are carefully read through and added in the manuscript based on the information.

 

4. The introduction is very short and devoted of recent literature to the topic. In Line 39-42, authors should clarify that “lung cancer is divided into two broad histologic classes: small-cell lung carcinomas (SCLC) and non-small lung cancer (NSCLC). NSCLC is further classified into three phenotypes, including adenocarcinoma...etc. There is also need to explore the therapeutic strategies in LC. Much progress has been achieved during last decade including combination treatments with chemo+ IO and targeted therapies for mutated patients like EGFR/ALK/ROS1/KRAS pts.

Responses: The introduction have been modified with data on lung cancer and its types. Studies indicating the progress of lung cancer has also been added.  

5. Please put more focus on the progress during last years, and despite that to mention that the prognosis still dismal. Also, smoking increases lung cancer but not all types of lung cancer. For example, some lung cancer patients harbouring EGFR mutations do not smoke (Please refer to Healthcare (Basel). 2022 Dec; 10(12): 2501). The novelty of this paper is very weak. There are some reviews/systematic reviews of its kinds (2021 Sep; 11(9): 630; Int J Mol Sci. 2022 May 17;23(10):5602). How this review extends reader understanding of the topic. What is new? What this review adds? This should be clearly explored at the end of the section.

Response: Section 8 focusing on the metabolomics of lung cancer in smokers and non-smokers are discussed.  The last section has been modified with the importance, aim and the future prospective of this review.

6. The method section is missing. Authors reviewed several studies but it is not clear how these studies were chosen for inclusion in the review. The section should include search terms, databases, years conducted, study type (vivo/vitro), inclusion/exclusion criteria…etc.

 

Response: A small paragraph on search criteria is explained in the section 10.

 

7. There is need to include an additional section about metabolomic-based biomarkers for lung cancer smokers and non-smokers. There are several studies discussed this point.

 

Response:  Section 8 on Metabolomic-based biomarkers for lung cancer smokers and non-smokers has been included in the manuscript.

 

8. Please do not include references in the conclusion.

 

Response:  Data with references has been removed and the conclusion has been modified.

 

Round 2

Reviewer 3 Report

Dear Authors,

The paper has significantly improved by these revisions. I have only two  comments.

1. Search strategy should be placed as section 2 not section 10.

2. Please follow the journal guidelines for referencing.

 

Author Response

Reviewer 3:

Comments and Suggestions for Authors

Dear Authors,

The paper has significantly improved by these revisions. I have only two comments.

1. Search strategy should be placed as section 2 not section 10.

Response: Thanks for your comments. We corrected the sentence.

2. Please follow the journal guidelines for referencing.

Response: Thanks for your comments. We updated the reference for MDPI format. .