Review for 10.1186/s12876-025-03643-2 (2025)

Title: Expression and prognostic significance of CD93 in blood vessels in colorectal cancer: an
immunohistochemical analysis of 134 cases
Version: 1 Date: 27 Dec 2024
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-The introduction states that "high CD93 expression indicates normalization of blood vessels,"
but this concept could benefit from more explanation. It might be useful to briefly discuss the
mechanisms by which CD93 might promote vascular normalization (e.g., through endothelial
cell stabilization or influence on vascular permeability) to provide readers with a clearer
biological rationale for this hypothesis.
-While the introduction briefly discusses studies on CD93 in nasopharyngeal carcinoma and
kidney cancer, a more in-depth review of CD93 in other cancers, particularly CRC, would
provide a stronger rationale for investigating this protein in CRC. This could help highlight why
CD93 is an interesting target and what aspects of CRC make it a particularly relevant cancer
to study in this context.
-While anti-VEGF therapy is mentioned, it would be useful to briefly discuss more recent or
ongoing efforts to target tumor vasculature beyond VEGF inhibition, such as targeting other
molecules involved in endothelial cell function or immune cell infiltration. This would provide
a broader scope and underscore the importance of investigating new vascular targets like CD93.
-The process of creating the tissue microarray (TMA) is well described, but the section could
benefit from more detail about the process of tissue selection. For example, were all tissue cores
selected from the same tumor area, or was sampling from multiple tumor regions performed?
This could be important for ensuring that the expression of CD93 is representative of the entire
tumor vasculature.
-The methodology for determining "high" vs. "low" expression of immune cells (CD4+, CD8+,
CD68+, CD80+) is mentioned, but more clarity on how the cut-off value is determined
(e.g., based on the median number of cells or a specific threshold) would be helpful.
Additionally, specifying how the three randomly selected areas are chosen would help assess
the representativeness of the measurements.
-The authors mention that CD93 plays different roles in different cancers (both poor and
favorable prognostic roles depending on the tumor type), but they do not fully address why
CD93 might have divergent prognostic implications across cancers. A more detailed discussion
of the factors that might determine whether CD93 acts as a negative or positive prognostic
factor (e.g., tumor microenvironment, molecular subtypes) would provide deeper insight into
the complexities of CD93 as a biomarker. This could help to clarify how CD93’s role in CRC
might differ from its role in other cancers.
-The authors mention that CD93 promotes macrophage and dendritic cell infiltration but do not
address the lack of correlation with T cell infiltration (CD4+ and CD8+). While they suggest
that this discrepancy may be due to sample size, a more in-depth discussion of this finding could
be helpful. For example, are there other immune cells (such as regulatory T cells or neutrophils)
that might be affected by CD93 in CRC? Moreover, how do macrophage and dendritic cell
infiltration influence tumor immunity and patient outcomes? Expanding on these points could
provide a more comprehensive understanding of CD93’s immune modulation in CRC.