Role of adamalysin proteases in modulations of tumor microenvironment and premetastatic niches - 04/04/15

Metastasis is the predominant cause of death in patients with cancer and reach relatively frequently specific secondary target organs such as the lungs. According to the “seed and soil” paradigm, these blood-borne metastases can be favored by a permissive microenvironment in these organs promoting tumor cells arrival and metastases growth.

Inflammation seems to play a role in the formation of a permissive microenvironment in different organs. The influence of individual inflammatory cell type in the premetastatic niches is less known.

Proteases of the Adamalysin family (ADAM and ADAMTS) are implicated both in various physiologic and in pathologic processes such as cancer. As these enzymes are known to be able to induce the cleavage and modification of the biological activity of various biological factors, they could be considered as molecular players that could potentially link the inflammation to tumor progression and metastases formation.

During this study, we analyzed the differential expression of ADAM/ADAMTS at a premetastatic stage in the lung parenchyma of mice bearing distant primary tumors.

Using balb/c mice injected intradermally in each flank with 2×105 Luciferase+ 4T1 tumoral cells and sacrified at days 3, 7, 9, 14, 21 and 26 after injection, we report an emergence of detectable metastasis at day 21 by Xenogen IVIS^® and histological lung sections analysis. Tumor-bearing mice quickly display a neutrophilic inflammation (already after 7days) in lung parenchyma and in the broncho-alveolar lavages. As we intended to assess the potential contribution of adamalysins in the premetastatic niche, we ensured the absence of tumor cells in the lungs and chosen after different experiments to perform our analysis on the lungs of mice sacrificed on day 7. At day 7, mice already display premetastatic niches characterics such as an accumulation of lysyl oxidase, MMP-9 and crosslinked collagen IV into the lungs. Finally, we showed an increase of ADAM-8 and -17 expression at a premetastatic stage into the lungs of tumour-bearing mice compared to the control mice.

In this study, we determined the time course of lung metastases for 4T1 cells after intradermal injection. We report that distant primary tumors induce an accumulation of neutrophils and an increase of ADAM-8 and -17 into the lungs before the metastases formation.

We will determine the pulmonary stromal cells responsible of ADAM-8 and -17 modulations.