Oncogenic Properties of Apoptotic Tumor Cells in Aggressive B Cell Lymphoma

Abstract

SummaryBackgroundCells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects.ResultsHere, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma.ConclusionsIn addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy.

High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

“…We present a combined analysis of transcriptome and proteome data to compare lymphoma-educated to M-CSF-differentiated Mφ. We extend recent data and models, which have proposed CXCL13, CCL5, and M-CSF as central players in the interaction of HL cells with Mφ (Carey et al, 2017;Casagrande et al, 2019;Ford et al, 2015;Locatelli et al, 2018;Ruella et al, 2017;Scott and Steidl, 2014;Tudor et al, 2014). We demonstrate that Jak/STAT signaling and, especially, IL13 are involved in the regulation of the expression of MRC1 and the abundance of CD206 on the surface of HL-educated Mφ.…”

A fate worse than death: apoptosis as an oncogenic process

“…Indeed, supporting this idea, inhibiting apoptosis, either through ectopic BCL-2 expression or loss of PUMA expression delays leukemia progression in mouse models of MDS 59,60 . As the authors suggest, if these findings hold These results, together with transcriptomic and in vitro co-culture experiments led the authors to propose a model whereby tumour cell apoptosis reprogram TAM towards a wound-healing type response that fuels tumourigenesis 68 .…”

Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages

“…Likewise, numerous studies in several regenerative model organisms including Hydra, planarians, newt, zebrafish, Xenopus and mammals have validated the concept of caspase-driven AiP (reviewed in [9, 10]). Furthermore, AiP may also be a contributing factor for the development of cancer and drug resistance [11–14]. …”