Professor Christopher D Gregory
Christopher D Gregory's lab aims to understand the mechanisms by which apoptotic tumour cells condition the tumour micro-environment.
- MRC Centre for Inflammation Research
- Research Theme: Immune Modulation and Regulation of Inflammation, Tissue Remodelling and Regeneration
- Margaret Paterson - Research Fellow (email)
- Lynsey Melville - Technician (email)
- Catherine Lynch - Optima PhD student (co-supervised with Dr Colin Campbell, School of Chemistry) (email)
- Maria Panagopoulou - Optima PhD student (email)
We aim to understand the mechanisms by which apoptotic tumour cells condition the tumour micro-environment. Specifically, our work seeks to define:
1. the mechanisms underlying the selective recruitment of mononuclear phagocytes to high-grade tumours in which cell death by apoptosis is frequent,
2. the effects dying cells exert on their viable neighbours - including phagocytes and tumour cells - and the molecular players involved in promoting tumour establishment and growth, and
3. novel anti-cancer therapeutic targets based around altering the innate immune responses against apoptotic cells.
Cell loss is a widespread feature of malignant tumours. In certain non-Hodgkin's lymphomas (NHL), prototypically Burkitt's lymphoma (BL), the cell death programme, apoptosis, is constitutively active such that net tumour growth results from a fine balance between cell birth and cell death. These lymphomas display a 'starry-sky' appearance that is generated by large numbers of infiltrating macrophages. Interactions between apoptotic cells and macrophages are known to be associated with anti-inflammatory and reparative responses. We hypothesise that apoptosis is an essential process in the pathogenesis of such lymphomas because the apoptotic component of the tumour-cell population (a) attracts and modulates macrophages to support net tumour growth, and (b) inhibits anti-tumour potential of granulocytes by suppressing their infiltration of starry-sky NHL.
Approaches and Progress
We have established that the CX3C chemokine, fractalkine (FKN), is released by apoptotic BL cells to attract macrophages and we propose that this chemokine and its receptor CX3CR1 play important roles in macrophage recruitment and activation in these lymphomas. We have also demonstrated that apoptotic lymphoma cells produce lactoferrin (LTF) that inhibits granulocyte migration. In addition, we have found that endogenous LTF promotes lymphoma cell growth in vitro. Taken together with the known inhibitory effects of granulocytes on lymphoma growth, these results identify LTF as a potentially important promoter of lymphoma growth in vivo. Using mouse models of starry-sky NHL, we are extending these studies to determine how apoptotic lymphoma cells contribute to the pathogenesis of NHL through effects on phagocytes. We plan to (1) define the importance of FKN and other chemokines in regulating the infiltration of tumour-associated macrophages (TAM), (2) elucidate the activation state of TAM that is driven by apoptotic lymphoma cells via FKN- and LTF-dependent and -independent mechanisms and (3) assess the efficacy of targeting FKN and LTF for therapeutic gain. The results of this research will have important implications for all tumours in which apoptosis is prominent.
High-grade cancers often contain large numbers of dying tumour cells alongside those that proliferate, the balance of cell-birth versus cell-death favouring net tumour growth. We believe that different categories of normal white blood cells 'sense' these dying cells and are either attracted to the tumours to help them to grow or are excluded from the tumours to prevent their destruction. Our research will define the mechanisms by which white cells invade malignant tumours, and aims to identify novel targets that may be used to treat cancers in the future by controlling their infiltration by normal blood cells and encouraging the dying cells in the tumour to activate the white blood cells to become tumour-destructive. Our understanding of how dead cells affect their viable neighbours will also help to improve the production of therapeutic cells and protein medicines in culture.
Postgraduate Director for the MRC Centre for Inflammation Research
Sources of Funding