Abstract
The tumor microenvironment is a dynamic and interactive supporting network of various components, including blood vessels, cytokines, chemokines, and immune cells, which sustain the tumor cell’s survival and growth. Murine models of lymphoma are useful to study tumor biology, the microenvironment, and mechanisms of response to therapy. Lymphomas are heterogeneous hematologic malignancies, and the complex microenvironment from which they arise and their multifaceted genetic basis represents a challenge for the generation and use of an appropriate murine model. So, it is important to choose the correct methodology. Recently, we supported the first evidence on the pro-oncogenic action of IBTK in Myc-driven B cell lymphomagenesis in mice, inhibiting apoptosis in the pre-cancerous stage. We used the transgenic Eμ-myc mouse model of non-Hodgkin’s lymphoma and Ibtk hemizygous mice to evaluate the tumor development of Myc-driven lymphoma. Here, we report that the allelic loss of Ibtk alters the immunophenotype of Myc-driven B cell lymphomas, increasing the rate of pre-B cells and affecting the tumor microenvironment in Eμ-myc mice. In particular, we observed enhanced tumor angiogenesis, increasing pro-angiogenic and lymphangiogenic factors, such as VEGF, MMP-9, CCL2, and VEGFD, and a significant recruitment of tumor-associated macrophages in lymphomas of Ibtk+/- Eμ-myc compared to Ibtk+/+ Eμ-myc mice. In summary, these results indicate that IBTK haploinsufficiency promotes Myc tumor development by modifying the tumor microenvironment.
Highlights
The chemokine system plays a key role in cancer-related inflammation involved in all stages of tumor development
Eμ-myc transgenic mice are widely used as a preclinical model of Myc-dependent B-lymphomagenesis [13,14]
We analyzed the effect of IBTK haploinsufficiency in B-lymphoma by taking advantage of Eμ-myc transgenic mice, a preclinical model of non-Hodgkin’s lymphoma
Summary
The chemokine system plays a key role in cancer-related inflammation involved in all stages of tumor development. Chronic inflammation in the tumor microenvironment contributes to the progression of many cancer types [1,2,3]. It is widely recognized that chronically activated immune cells sustain tumor growth and survival. It is clear that chronically activated immune cells can promote tumor growth and facilitate tumor survival. Macrophages are typically the main inflammatory component, but a variety of tumor-infiltrated immune cells can participate in tumor promotion [6]. It was shown that the tumor microenvironment (TME) composition as well as its functionality are tissue dependent and context dependent [9]. Whereas each mouse model may clarify the molecular mechanism of lymphoma, evaluation schema for mouse tumors have not yet been standardized [10]
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