The expression of members of the cysteine cathepsin (Cts) family of proteases in tumours is associated with advanced disease and poor prognosis. Gocheva, Wang and colleagues assessed cathepsin activity during the stages of tumour development in the RIP1-Tag2 (RT2) mouse model of pancreatic islet cell tumorigenesis. They found that hyperplastic islets had little or no cathepsin activity and that cathepsin activity substantially increased once preneoplastic lesions had undergone the angiogenic switch. Of the cells with high cathepsin activity, 92.5% were F4/80+ macrophages, which expressed CTSB, CTSC, CTSS and to a lesser degree CTSL. In advanced-stage tumours cathepsin activity was increased in TAMs adjacent to blood vessels and at the invasive front of the tumour.
To assess the importance of the cathepsins in tumour progression the authors conducted a series of bone marrow reconstitution experiments. Prior to neoplastic development, RT2 mice were lethally irradiated and transplanted with haematopoietic cells in which Ctsb, Ctsc, Ctsl or Ctss was deleted. Tumours arising in RT2 mice transplanted with either Ctsb−/− or Ctss−/− bone marrow were significantly smaller, exhibited decreased vascularization and were significantly less invasive. Further experiments showed that Ctsb−/− or Ctss−/− primary bone marrow-derived macrophages (BMDMs) retained their ability to home and migrate to the tumour, but were unable to invade the extracellular matrix, which limited the ability of the neighbouring tumour cells to invade and migrate. So, how is increased cathepsin activity induced? The authors cultured bone marrow-derived cells (BMDCs) in conditioned media, supplemented with colony stimulating factor 1 to induce macrophage differentiation. They found that conditioned media from RT2 tumour cells induced cathepsin activity 2.6-fold in BMDMs, compared with conditioned media from preneoplastic or control cells, indicating that cells from established tumours secrete a factor that activates cathepsins in TAMs. Interleukin-4 (IL-4) levels were higher in the conditioned media from RT2 tumour cells, and culture of BMDCs with recombinant IL-4 significantly increased cathepsin activity in the resulting BMDMs. IL-4 is expressed by RT2 tumour cells, but T cells express this at a higher level in vivo. However, as tumour cells comprise ∼85% of the tumour mass and T cells <2%, the authors propose that tumour cells are the main source of IL-4. Moreover, analyses of samples from the pancreatic islets of RT2 mice revealed that IL-4 expression by tumour cells paralleled the increased cathepsin activity with advancing tumour development. Importantly, Il4−/−;RT2 mice developed tumours that had reduced cathepsin activity although TAMs were present.
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