Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis
, Salvatore Rizzi 1, Maria Rendina 1, Enzo Ierardi 1, Alfredo Di Leo 1 and Giuseppe Losurdo 1,*
Round 1
Reviewer 1 Report
Overall, the abstract provides a concise summary of familial adenomatous polyposis (FAP) and its aetiology, underlining the crucial role of the APC gene mutation in driving the progression of colorectal adenoma to cancer. Recent studies have found other mechanisms that contribute to this process, including modifications in gut microbiota composition, mucosal barrier immunology, and hormone signalling pathways, which are discussed in the abstract. These parameters represent possible therapeutic and chemopreventive targets for FAP.However, it would be advantageous to provide further information on the methodology employed in this review, such as the search strategy used to locate relevant literature and the inclusion/exclusion criteria utilised to select studies for analysis. Also, it would be beneficial to include more information on the scope of the review, such as whether it encompasses all systemic extraintestinal manifestations of FAP or focuses primarily on the pathogenesis of colorectal cancer. This abstract has the potential to give an instructive summary of current information regarding FAP and its aetiology if further details are included.
Author Response
Overall, the abstract provides a concise summary of familial adenomatous polyposis (FAP) and its aetiology, underlining the crucial role of the APC gene mutation in driving the progression of colorectal adenoma to cancer. Recent studies have found other mechanisms that contribute to this process, including modifications in gut microbiota composition, mucosal barrier immunology, and hormone signalling pathways, which are discussed in the abstract. These parameters represent possible therapeutic and chemopreventive targets for FAP.However, it would be advantageous to provide further information on the methodology employed in this review, such as the search strategy used to locate relevant literature and the inclusion/exclusion criteria utilised to select studies for analysis. Also, it would be beneficial to include more information on the scope of the review, such as whether it encompasses all systemic extraintestinal manifestations of FAP or focuses primarily on the pathogenesis of colorectal cancer. This abstract has the potential to give an instructive summary of current information regarding FAP and its aetiology if further details are included.
The present article is a narrative review, whose scope was to explore the genetic and environmental factors that may contribute to the development of CRC in FAP. Such details have been added in the text.
Reviewer 2 Report
see attached.
Comments for author File: 
Comments.pdf
Author Response
The manuscript “Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis” by Ditonno et al has attempted to review the Familial Adenomatous Polyposis (FAP) from the point of view of underlying mechanisms for the genesis as well as the potential factors that influence FAP. The review could be improved by making the following modifications: The authors at the outset discuss about the WNT pathway, catenin and role of APC in FAP formation. It would be helpful if the authors can provide a figure showing the pathway and the catenin as well as interaction of APC that leads to uncontrolled proliferation.
We added a new figure in the paper, as requested.
Presence of various cytokines are described in the tumor microenvironment. Since the authors are suggesting these as novel targets, the strategies that can be employed in this regard need to be discussed.
Unfortunately, cytokine modulation in tumor microenvironment is a poorly studied field in FAP patients. We reported a study showing that COX inhibition may increase levels of NAG-1 which, in turn, enhances apoptosis (Baek, S. J.; Kim, K.S; Nixon, J.B.; Wilson, L.C.; Eling, T.E. Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol. 2001 ;59(4):901-8), while sulindac, in a murine model of FAP, restored normal levels of apoptosis by downregulating prostaglandin E2 (Boolbol, S.K.; Dannenberg, A.J.; Chadburn, A.; Martucci, C.; Guo, X.J.; Ramonetti, J.T.; Abreu-Goris, M.; Newmark, H.L.; Lipkin, M.L.; et al. Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res. 1996;56(11):2556-60.)
Various studies have been described that showed the role of microbiota in FAP. Please provide a Table that lists the organism(s), impact on FAP and relevant reference.
We added a new table in the paper reporting the most important changes in microbiota composition, as requested.
Figure 1. It is not clear what the authors are attempting to convey. It would be preferable if each of the topics are expanded and preferably depicted in a manner that shows their interaction with each other. Also a detailed legend explaining the figure is needed.
The figure in object aims to summarize the main aspects (genetics, environmental, hormonal factors) that may contribute to the development of CRC in FAP. Therefore we changed the legend of the figure.
