Gram-Negative Bacterial Lipopolysaccharide Promotes Tumor Cell Proliferation in Breast Implant-Associated Anaplastic Large-Cell Lymphoma.

Maria Mempin,Honghua Hu,Nicola Kouttab,William P Adams,H Miles Prince,Karen Vickery,Anand K Deva,Marshall E Kadin,John W Morgan

doi:10.3390/cancers13215298

Abstract

Simple SummaryThe development of a rare cancer of the immune system (lymphoma) associated with breast implants has been increasingly reported around the world. It has been hypothesized that the cancer is triggered by inflammation from bacteria residing within the textured surface of these implants, transforming the lymphocytes of some genetically prone patients over many years. This study shows that bacteria rather than the implant itself can trigger activation and multiplication of these cancer cells in the laboratory, lending support that bacteria and their products play an important role in causation. The unique response of these cancer cells to bacterial antigen was dampened significantly in the presence of a Toll-like receptor 4 inhibitor peptide. This finding has significance for both cancer prevention and treatment.Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a distinct malignancy associated with textured breast implants. We investigated whether bacteria could trigger the activation and multiplication of BIA-ALCL cells in vitro. BIA-ALCL patient-derived BIA-ALCL tumor cells, BIA-ALCL cell lines, cutaneous ALCL cell lines, an immortal T-cell line (MT-4), and peripheral blood mononuclear cells (PBMC) from BIA-ALCL, capsular contracture, and primary augmentation patients were studied. Cells were subjected to various mitogenic stimulation assays including plant phytohemagglutinin (PHA), Gram-negative bacterial lipopolysaccharide (LPS), Staphylococcal superantigens enterotoxin A (SEA), toxic shock syndrome toxin-1 (TSST-1), or sterilized implant shells. Patient-derived BIA-ALCL tumor cells and BIA-ALCL cell lines showed a unique response to LPS stimulation. This response was dampened significantly in the presence of a Toll-like receptor 4 (TLR4) inhibitor peptide. In contrast, cutaneous ALCL cells, MT-4, and PBMC cells from all patients responded significantly more to PHA, SEA, and TSST-1 than to LPS. Breast implant shells of all surface grades alone did not produce a proliferative response of BIA-ALCL cells, indicating the breast implant does not act as a pro-inflammatory stimulant. These findings indicate a possible novel pathway for LPS to promote BIA-ALCL cell proliferation via a TLR4 receptor-mediated bacterial transformation of T-cells into malignancy.

Highlights

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a recently recognized distinct malignancy of T lymphocytes associated with textured breast implants used for both aesthetic and reconstructive surgery [1,2,3,4]
We investigated whether bacterially derived antigenic drivers would interact differentially with BIA-ALCL tumor cells as compared with tumor cells derived from other lymphomas and with peripheral blood mononuclear cells (PBMC) harvested from patients with BIA-ALCL, from patients having breast implants removed due to Cancers 2021, 13, 5298 capsular contracture, and from healthy control subjects without exposure to breast implants
Our detailed analysis of the relationship between patient-derived BIA-ALCL primary tumor cells and tumor cell lines to a variety of bacterially derived antigens showed that there is a unique, proliferative response to the presence of Gram-negative bacterial LPS. This is in contrast to tumor cells from the phenotypically similar cutaneous form of ALCL, a T-cell leukemia cell line (MT-4), and PBMC derived from patients who have been diagnosed with capsular contracture and from those who have not been previously exposed to breast implants

Summary

Introduction

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a recently recognized distinct malignancy of T lymphocytes associated with textured breast implants used for both aesthetic and reconstructive surgery [1,2,3,4]. The development of BIA-ALCL is likely to be a complex process resulting from an interplay of host, implant, and microbial factors, including the patient’s genetic background, immune response, the textured implant surface, and bacterial phenotype that leads to neoplastic lymphoid tissue progression. This could account for why some patients with biofilm infection around breast implants proceed to contracture and why others, less common, proceed to lymphocytic hyperplasia and BIA-ALCL

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