In-depth understanding of the role played by microenvironment components in the pathogenetic mechanisms leading to lymphoma onset and progression may lead to the identification of new therapeutic strategies for highly aggressive lymphoma.
To study the contribution of microenvironment components into lymphomagenesis, (a) Primary Effusion Lymphoma (PEL) is used as a model of B-cell lymphoma growing in body cavities, whereas (b) Adult T-cell Leukemia/Lymphoma (ATLL) is used as a model of an aggressive and diffused T-cell lymphoma.
It is well-known that the crosstalk between pre-malignant/malignant cells with stromal components may generate a microenvironment permissive to oncogenic progression. PEL is an aggressive, HHV8-driven, non-Hodgkin’s B-cell lymphoma with poor prognosis, growing as lymphomatous effusion in large body cavities. The peculiar intracavitary localization of this lymphoma implies a specific contribution of body cavities to PEL pathogenesis. ATLL, a peripheral T-cell malignancy, arises in only 2-5% of HTLV-1-infected persons decades after primary infection, suggesting that host factors contribute to ATLL onset. Little is known about the role of the microenvironment in the mechanisms triggering the development of this lymphoma.
By using a PEL/SCID mouse model, we demonstrated that the intracavitary targeting of the murine microenvironment with a lentiviral vector expressing murine interferon (IFN)-alpha exerts a significant anti-neoplastic activity. mIFN-alpha-treated murine mesothelial cells were found to induce apoptosis of PEL cells in a TRAIL-dependent manner. These data suggest that the interaction between lymphomatous and mesothelial cells lining the body cavities may play a key role in PEL growth control, and that mesothelial cells may be central to PEL pathogenesis (Blood 2009). Moreover, mesothelial cells may modify PEL cell turnover, increasing their proliferation and resistance to apoptosis, thus providing a milieu favorable to PEL progression (Mol Med 2014).
We found that the fibroblastic stromal component may trigger tumorigenesis of IL-2-independent HTLV-1-immortalized T-cells, inducing a transcriptional and secretory reprogramming relevant to ATLL pathogenesis, and established a new preclinical model mimicking the aggressive nature of ATLL lymphoma variant (Front Microbiol 2018). More recently, we demonstrated that the crosstalk with fibroblasts modulates the aggressiveness and plasticity of immortalized lymphomatous cells, leading to the enrichment in lymphoma-initiating cells (Int J Mol Sci 2021).
Conclusions and perspectives
In-depth understanding of interactions between tumor cells and mesothelium may suggest new approaches to improve the treatment not only of PEL but also of other intracavitary tumors, such as peritoneal carcinomatosis, the most common terminal feature of abdominal cancers.
Detailed characterization of the new preclinical ATLL model will shed light on the complex events enhancing lymphoma development in HTLV-1 carriers and will offer a more general target to prevent lymphoma development.
Characterization of the intrinsic or therapy-modulated profiles of EMP-related factors in highly aggressive tumors may shed light on the relevance of specific EMP pathways involved in tumor progression, leading to the identification of new diagnostic/prognostic markers and potentially novel targets for therapeutic intervention.
EMP in highly aggressive primary tumors and peritoneal metastases.
EMP is a complex and multifaceted embryonic process and its partial activation is an important driver of tumor progression. Some EMP-associated pathways are also linked to stemness properties, chemotherapy resistance and immunological behavior of tumor cells.
We previously demonstrated that cocultures of primary human mesothelial cells (HMC) with PEL-derived cell lines induce a myofibroblastic phenotype and an expression profile indicative of epithelial-mesenchymal transition (EMT) in HMC. Serosal membranes underwent a progressive thickening in a xenograft mouse model of PEL, with the appearance of mesenchymal-like cells during intracavitary PEL development. These data indicate that PEL cells may induce type 2 EMT in HMC, leading to fibrosis of serous membranes. Our findings provide new clues into the mechanisms involved in PEL progression and indicate new targets for tumors developing in the intracavitary milieu (Cancer Med 2014).
In collaboration with other IOV Units, we are presently defining sets of innovative EMP-related biomarkers with diagnostic and prognostic value in high-grade soft tissue sarcoma samples (Clin Cancer Res 2020), and in tumor samples of peritoneal metastases (PM). Moreover, we are characterizing the aggressive nature and the molecular and biological heterogeneity of primary tumor cultures derived from rarer PM undergoing CRS-HIPEC.
Conclusions and perspectives
In-depth understanding of the evolving role of EMP in tumor progression, cancer stemness and drug resistance may suggest new targets for therapeutic combinations and novel biomarkers with diagnostic and prognostic significance for highly aggressive tumors and peritoneal metastases.