Extracellular Events Involved in Cancer Cell–Cell Fusion

Round 1

Reviewer 1 Report

The authors present an extensive review that highlights the role of extracellular factors involved in cancer cell-cell fusion.

The review is well written and contains a wealth of information pertaining to potential extracellular mechanisms and scenarios leading to cancer cell-cell fusion such as the involvement of inflammation and inflammatory cytokines, the role of viruses, the pH factor and ions concentrations, hypoxic conditions, and the presence of exosomes. The review suggests the possible interactions between multiple factors leading to cancer cell fusion and weighs the potential importance of some factors relative to others. This is a good review that gives a comprehensive role of the extracellular environment in cancer cell fusion and will be of great interest for readers of IJMS and the scientific community as a whole on the mechanisms of cancer cell fusion that could impact cancer progression and metastasis.

Minor comment

Figure 2 is very complex and needs more labelling and stepwise description to guide the reader.

Author Response

Reviewer #1

We would like to thank the reviewer for taking the time to critically read the manuscript. Likewise, we are grateful for the helpful comments. In the following, we will respond to the comments point by point.

Comments and Suggestions for Authors

The authors present an extensive review that highlights the role of extracellular factors involved in cancer cell-cell fusion.

The review is well written and contains a wealth of information pertaining to potential extracellular mechanisms and scenarios leading to cancer cell-cell fusion such as the involvement of inflammation and inflammatory cytokines, the role of viruses, the pH factor and ions concentrations, hypoxic conditions, and the presence of exosomes. The review suggests the possible interactions between multiple factors leading to cancer cell fusion and weighs the potential importance of some factors relative to others. This is a good review that gives a comprehensive role of the extracellular environment in cancer cell fusion and will be of great interest for readers of IJMS and the scientific community as a whole on the mechanisms of cancer cell fusion that could impact cancer progression and metastasis.

Minor comment

Figure 2 is very complex and needs more labelling and stepwise description to guide the reader.

We are thankful for this helpful comment and we agree with the reviewer that the previous version of this figure was very complex and overloaded with information. In the revised manuscript the previous figure was split into now two separate figures. We hope that both figures are now clearer. Likewise, the legends have been revised.

Reviewer 2 Report

Extracellular events involved in cancer cell-cell fusion

Ijms_206019

Cell-cell fusion, both homotypic and heterotypic have important roles in the genesis and development of organisms and organs. A century old hypothesis and decades of studies point to cancer cell-cell fusion as having important impact on tumor progress. In recent years a number of teams have investigated cancer cell-cell fusion from various angles. Here in this review, Dittmar and Hass provide a thorough view, and needed insight, on mechanisms that may facilitate cancer cell fusion. Importantly, they look to the areas of developmental fusion to set the context for extracellular impacts that may underlie the fusion process. Overall, this is an important review, where many fusion reviews focus on physiologic relevance, Dittmar and Hass examine fusogenic mechanisms. There are only a few minor comments listed below.

General Comments:

1. It is important the include a statement eluding to the various types of cancer cell fusion indicating that there may not be conserved mechanisms for events in different context (i.e. for initiating events versus tumor progression; or across different organ sites, given that inflammatory microenvironments may differ broadly).

2. It is not know why cancer cells fuse, but it might be helpful to address this within the discussion.

3. The concept that cells must transit to a fusogenic state is important and needs some additional attention as to how they might do this.

Author Response

Reviewer #2

Open Review

We would like to thank the reviewer for taking the time to critically read the manuscript. Likewise, we are grateful for the helpful comments. In the following, we will respond to the comments point by point.

Cell-cell fusion, both homotypic and heterotypic have important roles in the genesis and development of organisms and organs. A century old hypothesis and decades of studies point to cancer cell-cell fusion as having important impact on tumor progress. In recent years a number of teams have investigated cancer cell-cell fusion from various angles. Here in this review, Dittmar and Hass provide a thorough view, and needed insight, on mechanisms that may facilitate cancer cell fusion. Importantly, they look to the areas of developmental fusion to set the context for extracellular impacts that may underlie the fusion process. Overall, this is an important review, where many fusion reviews focus on physiologic relevance, Dittmar and Hass examine fusogenic mechanisms. There are only a few minor comments listed below.

General Comments:

1. It is important the include a statement eluding to the various types of cancer cell fusion indicating that there may not be conserved mechanisms for events in different context (i.e. for initiating events versus tumor progression; or across different organ sites, given that inflammatory microenvironments may differ broadly).

Answer: We’re grateful for this important point which we have addressed in combination with point 2. in the Discussion (line 599 to 604)

2. It is not know why cancer cells fuse, but it might be helpful to address this within the discussion.

Answer: (see above point 1.)

3.The concept that cells must transit to a fusogenic state is important and needs some additional attention as to how they might do this.

Answer: We have included a passage in the Discussion to emphasize potential requirements for a fusogenic state.