Several years ago we became interested in parallels between repair and cancer. We have investigated the related responses of innate immune cells to wounds and to very early initiating clones of pre-neoplastic cells and showed that in both instances, hydrogen peroxide and other DAMPs are key attractant signals, and that, as a clone of pre-neoplastic cells gets larger, the inflammatory response resembles more that of a chronic non-healing wound.  Live imaging studies indicate that whilst both neutrophils and macrophages can engulf and clear the pre-neoplastic cells, the overall consequence of an innate immune cell presence at the site of these clones is that they grow faster suggesting that immune cells deliver trophic growth signals to these pre-cancerous cells. We subsequently showed that one of these trophic factors was the prostaglandin, PGE2, which suggests that one of the mechanisms of action of aspirin, which blocks COX-mediated synthesis of PGE2, and has been proven by previous epidemiological studies to be a cancer preventative, might be to starve these early pre-neoplastic cells of trophic input from innate immune cells.    

This is a TedMed talk from 2014 when Paul Martin was talking about early modelling of cancer in zebrafish and coincidently, at the same time he was having chemo for cancer. 

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We have now begun to test how the acute inflammatory response that occurs at sites of tissue biopsy or cancer surgery might impact on pre-neoplastic or more established cancer cells that remain at the site of surgery and, using the zebrafish model, we’ve shown that neutrophils are distracted away from a wound towards any nearby pre-cancerous cells, leading to their increased proliferation.  This work clearly indicates risk factors associated with any clinical procedure, for example, a tissue biopsy or a surgery, or radiotherapy, which leads to tissue damage in the vicinity of cancer cells. Our lab is currently investigating whether this is true for cancers other than melanoma.

The first of our “scribble videos” pioneered by Laura Ward to explain our observation that tissue wounding and the resulting inflammatory response can exacerbate cancer growth in translucent zebrafish and in human melanoma patients.

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We are curious also how inflammatory cells are able to access the newly developing clones of pre-neoplastic cells because these sit within an epithelium which in turn sits on a barrier layer, the basement membrane.  We have recently established that there are weakspots in this matrix barrier zone and these are opportunistically used by neutrophils and macrophages as portals to access the cancer and this, in turn, dictates which cancers will grow the fastest through exposure to inflammation-derived growth signals.    

One of our most recent "scribble videos" explains how innate immune cells are able to access very early developing cancer clones in the epithelium by breaching the extracellular matrix basement membrane. 

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We have also begun to investigate ways we might reprogramme the cancer inflammatory response away from its nurturing behaviour and towards a more pro-inflammatory, tumoricidal profile so that when inflammatory cells are recruited to cancer sites, they can better kill off cancer cells and drive tumor shrinkage. We have shown that this switch from pro-cancer to anti-cancer phenotype in inflammatory cells can be triggered either by infection (as pioneered over a century ago by Coley), or through miniature artificial cells called protocells that are potentially more applicable as therapeutics in the clinic. For the first time, we have used protocells to specifically deliver ‘reprogramming’ cargoes (in this case, anti-miR223) to zebrafish macrophages (and neutrophils) because these immune cells are phagocytes. We showed that macrophages can uptake circulating protocells (see 3D Imaris rendering) containing this reprogramming cargo and, as a consequence, effectively maintain a pro-inflammatory, anti-cancer state, leading to a reduction in size of zebrafish adult melanomas. This protocell strategy offers the promise for the clinic because we demonstrated that cultured human macrophages can also be effectively reprogrammed when exposed to our protocells with anti-miR223 cargo.  

Our latest “scribble video” summarising how we reprogrammed innate immune cells with pro-inflammatory-inducing protocells to promote tumor shrinkage.

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Most recently, we have shown that microclots induced in zebrafish larval vessels can be the foci for cancer cell extravasation and our movies reveal a pivotal role for immune cells here too.

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Antonio, N, Bønnelykke-Behrndtz, ML, Ward, LC, Collin, J, Christensen, IJ, Steiniche, T, Schmidt, H, Feng, Y & Martin, P 2015, 'The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer', EMBO Journal, vol. 34, no. 17, pp. 2219-36. https://doi.org/10.15252/embj.201490147

Van Den Berg, M, MacCarthy-Morrogh, L, Carter, D, Morris, J, Ribeiro Bravo, I, Feng, Y & Martin, P 2019, 'Proteolytic and Opportunistic Breaching of the Basement Membrane Zone by Immune Cells during Tumor Initiation', Cell Reports, vol. 27, no. 10, pp. 2837-2846.e4. https://doi.org/10.1016/j.celrep.2019.05.029

MacCarthy-Morrogh, L, Martin, P 2020, 'The hallmarks of cancer are also the hallmarks of wound healing', Science Signaling, vol. 13, no. 648. https://doi.org/10.1126/scisignal.aay8690

López-Cuevas, P, Cross, SJ, Martin, P 2021, 'Modulating the Inflammatory Response to Wounds and Cancer Through Infection', Frontiers in Cell and Developmental Biology. https://doi.org/10.3389/fcell.2021.676193

López-Cuevas, P, Xu, C, Severn, CE, Oates, TCL, Cross, SJ, Toye, AM, Mann, S, Martin, P 2022, 'Macrophage Reprogramming with Anti-miR223-Loaded Artificial Protocells Enhances In Vivo Cancer Therapeutic Potential', Advanced Science. https://doi.org/10.1002/advs.202202717 

Ward, J, Martin, P 2023, 'Live-imaging studies reveal how microclots and the associated inflammatory response enhance cancer cell extravasation', Journal of Cell Science vol. 136, no. 18. https://doi.org/10.1242/jcs.261225