Peritoneal Metastasis as a Distinct Biological Entity: Mechanisms, Microenvironment, and Therapeutic Implications

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review entitled “Peritoneal metastasis as a distinct biological entity: mechanisms, microenvironment, and therapeutic implications” by Serdar Gumus, Ugur Topal, Ibrahim Cogal and Cem Kaan Parsak is devoted to clinical, molecular, and immunological patters of peritoneal metastases (PM). This review summarizes the major routes of PM development and emphasizes how these pathways converge through shared biological mechanisms such as epithelial-mesenchymal transition (EMT), adhesion signaling, extracellular matrix remodeling, and tumor-immune cell interactions.

Despite the favorable impression, there are several comments about the manuscript:

1. The main mechanisms cited in the manuscript for peritoneal metastasis include epithelial-mesenchymal transition (EMT), adhesion signaling, extracellular matrix remodeling, and tumor-immune cell interactions. However, these are general mechanisms for metastases development in different organs. How can you comment on this point? What are the special features that differing peritoneal metastasis from any other?
2. It is necessary to more clearly distinguish between primary and secondary peritoneal metastases and indicate what the difference is between them, if any (Section 2).
3. Are there animal models of peritoneal metastasis in addition to cell organoid models (Section 4)?
4. What do the numbers 3.1.3 inside the frame in Figure 1 mean? Does this mean that part of the figure is borrowed from some source?

Author Response

Reviewer 1

Comment 1:
The main mechanisms cited in the manuscript for peritoneal metastasis include epithelial–mesenchymal transition (EMT), adhesion signaling, extracellular matrix remodeling, and tumor–immune cell interactions. However, these are general mechanisms for metastasis development in different organs. How can you comment on this point? What are the special features that differing peritoneal metastasis from any other?

Response:
We thank the reviewer for this insightful comment. We agree that EMT, adhesion signaling, extracellular matrix remodeling, and immune regulation are not exclusive to peritoneal metastasis and represent common metastatic programs across multiple organ sites. To address this important point, we have added a new paragraph in Section 3.1.3 ("Common Biological Programs") highlighting features that distinguish peritoneal metastasis from other metastatic environments. Specifically, we discuss transcoelomic dissemination, mesothelial-to-mesenchymal transition (MMT), omental milky spots as specialized immune microcompartments, adipocyte-mediated metabolic support, and pre-metastatic niche priming within the peritoneal cavity. These additions emphasize how common metastatic mechanisms are uniquely shaped by the anatomical, immunological, and metabolic characteristics of the peritoneal environment.

Comment 2:
It is necessary to more clearly distinguish between primary and secondary peritoneal metastases and indicate what the difference is between them, if any (Section 2).

Response:
We thank the reviewer for this valuable suggestion. To clarify this distinction, we expanded Section 2 by adding a dedicated paragraph describing the biological origin, disease evolution, and clinical behavior of primary and secondary peritoneal malignancies. The revised text highlights that primary peritoneal malignancies arise from the peritoneal lining itself, whereas secondary peritoneal disease represents metastatic dissemination from primary tumors such as colorectal, gastric, appendiceal, or ovarian cancers. We also discuss how these differences influence biological behavior and therapeutic decision-making.

Comment 3:
Are there animal models of peritoneal metastasis in addition to cell organoid models (Section 4)?

Response:
We appreciate this important observation. In response, we expanded the Future Perspectives section by adding a paragraph discussing currently available animal models of peritoneal metastasis. The revised manuscript now describes syngeneic, orthotopic, and patient-derived xenograft (PDX) models and their role in studying metastatic implantation, host–tumor interactions, and preclinical evaluation of intraperitoneal therapies, including HIPEC and PIPAC. We also emphasize the complementary roles of organoid platforms and animal models in translational PM research.

Comment 4:
What do the numbers 3.1.3 inside the frame in Figure 1 mean? Does this mean that part of the figure is borrowed from some source?

Response:
We thank the reviewer for this observation. The “3.1.3” label was unintentionally retained during figure preparation and referred to an internal subsection heading used during manuscript drafting. It was not intended to indicate material adapted or reproduced from any external source. To avoid confusion, the entire label has been removed from the revised figure. Figure 1 is an original illustration created by the authors.

Reviewer 2 Report

Comments and Suggestions for Authors

 

The manuscript provides a valuable and up-to-date review of the biology of peritoneal metastases. However, several biological aspects require further clarification, the clinical evidence regarding HIPEC should be discussed in a more critical manner, and some overly categorical statements should be moderated. After addressing the points outlined below, the manuscript will represent a useful resource for readers interested in translational oncology and the management of peritoneal malignancies.

1.      Ambiguous role of IL-6

Lines 184–185 and 246–249

In Section 3.2, the authors suggest a suppression of IL-1 and IL-6, whereas later in the manuscript IL-6 is described as a key mediator of tumor progression.

Although the authors attempt to reconcile this apparent discrepancy (lines 245–250), a more detailed explanation would be helpful, particularly regarding:

• the differences between the pre-metastatic niche and established metastasis stages,
• the context-dependent functions of IL-6 during disease progression,
• the distinct cellular sources of IL-6 (e.g., cancer-associated fibroblasts, macrophages, and tumor cells).

In its current form, this issue may be confusing for readers.

 

2.      RECIST criteria and peritoneal metastases

Lines 328–330

The authors should consider adding one or two sentences explaining why conventional RECIST criteria have limited applicability in peritoneal metastases, including the diffuse growth pattern of the disease, irregular peritoneal implants, and the frequent absence of measurable target lesions.

 

3.      Insufficient discussion of the controversies surrounding HIPEC

Lines 47–55, 136–142, and 294–296

The manuscript emphasizes the benefits of CRS-HIPEC; however, it does not adequately address the findings of major randomized clinical trials, particularly:

• PRODIGE 7,
• COLOPEC,

As currently written, readers may gain the impression that HIPEC's efficacy is broadly established across most forms of peritoneal metastases.

The authors are encouraged to include a separate paragraph summarizing:

• the lack of overall survival benefit observed in the PRODIGE 7 trial,
• the important differences in outcomes among appendiceal neoplasms, peritoneal mesothelioma, colorectal cancer, and gastric cancer,
• the ongoing debate regarding the relative contribution of HIPEC itself versus complete cytoreductive surgery (CRS) to the observed clinical outcomes.

 

Author Response

Reviewer 2

Comment 1:
Ambiguous role of IL-6

In Section 3.2, the authors suggest a suppression of IL-1 and IL-6, whereas later in the manuscript IL-6 is described as a key mediator of tumor progression. Although the authors attempt to reconcile this apparent discrepancy, a more detailed explanation would be helpful, particularly regarding the differences between the pre-metastatic niche and established metastasis stages, the context-dependent functions of IL-6 during disease progression, and the distinct cellular sources of IL-6.

Response:
We thank the reviewer for this thoughtful comment. We agree that the role of IL-6 requires further clarification to avoid potential confusion. To address this issue, we expanded Section 3.3.2 by adding a dedicated paragraph explaining the stage-dependent and context-dependent functions of IL-6. The revised text now distinguishes between pre-metastatic niche formation, where tumor-derived exosomal signaling may contribute to an immunoregulatory environment, and established metastatic disease, where IL-6 is predominantly produced by cancer-associated fibroblasts, macrophages, and tumor cells and promotes proliferation, epithelial–mesenchymal transition, angiogenesis, and therapy resistance through STAT3 signaling. We believe these additions provide a clearer framework for understanding the dynamic role of IL-6 during PM progression.

Comment 2:
RECIST criteria and peritoneal metastases

The authors should consider adding one or two sentences explaining why conventional RECIST criteria have limited applicability in peritoneal metastases, including the diffuse growth pattern of the disease, irregular peritoneal implants, and the frequent absence of measurable target lesions.

Response:
We appreciate this valuable suggestion. In response, we expanded the Future Perspectives section by adding a short explanation regarding the limitations of RECIST in PM. The revised manuscript now highlights that PM frequently manifests as diffuse serosal thickening, omental caking, and scattered small implants that often fail to meet conventional RECIST definitions of measurable target lesions. We further note that these characteristics can complicate radiological response assessment and may underestimate clinically meaningful treatment effects.

Comment 3:
Insufficient discussion of the controversies surrounding HIPEC

The manuscript emphasizes the benefits of CRS-HIPEC; however, it does not adequately address the findings of major randomized clinical trials, particularly PRODIGE 7 and COLOPEC. As currently written, readers may gain the impression that HIPEC's efficacy is broadly established across most forms of peritoneal metastases.

Response:
We thank the reviewer for this important observation. We agree that a more balanced discussion of the current evidence surrounding HIPEC was warranted. Accordingly, we added a dedicated paragraph in the Future Perspectives section addressing ongoing controversies in the field. The revised text now discusses the findings of the PRODIGE 7 trial, which did not demonstrate an overall survival benefit for oxaliplatin-based HIPEC following complete cytoreduction in colorectal PM, as well as the mixed results reported by the COLOPEC and PROPHYLOCHIP studies. We also emphasize that the clinical benefit of HIPEC is not uniform across all tumor types and that outcomes differ substantially between appendiceal neoplasms, peritoneal mesothelioma, colorectal cancer, and gastric cancer. Finally, we highlight the ongoing debate regarding the relative contributions of CRS and HIPEC to observed clinical outcomes and the increasing focus on biomarker-guided patient selection.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have fully responded to all questions and comments. The manuscript can be published in its current form.