Abstract
Author SummaryThe translucency of zebrafish larvae allows us to live image the earliest dynamic interactions between host innate immune cells and oncogene-transformed cell clones as they first establish themselves as the precursors of full-blown cancer. These early associations manifest via cytoplasmic tethers between an immune cell and a transformed cell, and occasional phagocytic engulfment. Immune cells are first attracted to transformed cells at surprisingly early stages, before transformed cells have had a chance to form clones and are thus still singletons or doublets. We show that the key attractant is hydrogen peroxide (H2O2), which was also recently shown to be the essential early damage signal responsible for drawing neutrophils to wounds. Tissue transplantation experiments allow us to test which cells are responsible for generating the H2O2 attractant, and we show that both transformed cells and their otherwise healthy neighbors contribute. Blocking H2O2 synthesis, either pharmacologically or by morpholino-mediated knockdown of DUOX, the enzyme responsible for H2O2 synthesis in larval skin, very significantly reduces the numbers of neutrophils and macrophages drawn to transformed cell clones, and this results in reduced numbers of transformed cells, suggesting that innate immune cells play a trophic and/or support role in early transformed cell growth.
Highlights
Cancers originate from one or a few clones of transformed cells that gain a growth advantage over neighboring normal cells, which, in turn, enables them to invade the host microenvironment and form a tumor [1,2]
The translucency of zebrafish larvae allows us to live image the earliest dynamic interactions between host innate immune cells and oncogene-transformed cell clones as they first establish themselves as the precursors of fullblown cancer
We show that the key attractant is hydrogen peroxide (H2O2), which was recently shown to be the essential early damage signal responsible for drawing neutrophils to wounds
Summary
Cancers originate from one or a few clones of transformed cells that gain a growth advantage over neighboring normal cells, which, in turn, enables them to invade the host microenvironment and form a tumor [1,2]. Inflammation is a crucial function of the innate immune system that protects host tissues against dangerous insults that are detrimental to tissue homeostasis, including wound damage and pathogen invasion [11]. As triggered by wounding, is a rapid and self-limiting process: chemical mediators are induced in a tightly regulated sequence, and innate immune cells move in and out of the affected area, destroying infectious agents, and delivering growth factors and other signals that aid in repairing the damaged tissue [12]. When does the host first recognize transformed cells, and how do they interact? Answering this question begs a model that allows easy live, in vivo observation of these events
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