Extracellular Vesicles as a Proposed Third Signalling Component of Paget’s Seed‐And‐Soil Theory

Paget’s seed-and-soil theory explains why cancer spreads to some organs and not others. It describes a travelling tumour cell that meets a receptive organ. It does not say how the organ becomes receptive. Extracellular vesicles (EVs) carry proteins and RNA between cells, and in experimental models tumour EVs can prepare a distant organ before tumour cells arrive [1–6]. We propose EVs as a third signalling component of Paget’s scheme: a signal that can travel ahead of the cell. It does not replace the seed, and preparing a tissue is not metastasis. We also place two further findings in this frame: metastases can differ genetically from their primary tumours [7,8], and metastatic progression is often linked to new blood vessels [9,10].The framework separates four levels of inference: an effect of an EV-containing sample, an effect shown to depend on EVs, a state that outlasts EV exposure, and a named mechanism for that state. Among the claims proposed here, EV-mediated tissue preparation has the strongest support. Yet most of that support sits at the first level, because few studies tested EV dependence with depletion and add-back controls. Two optional branches ask whether EVs can leave a lasting state in the receiving cell, through a change in protein shape (Route A) or through RNA reaching the genome (Route B). Dropping either branch leaves the core intact. Each claim is graded by its evidence and paired with the result that would prove it wrong.