Although the standard treatment for the patients with recurrent and metastatic prostate cancer (CaP) is androgen deprivation therapy, castration-resistant prostate cancer (CRPC) eventually emerges. Our previous report indicated that bone morphogenetic protein 6 (BMP6) induced CRPC via tumour-infiltrating macrophages. In a separate line of study, we have observed that the WNT5A/BMP6 loop in CaP bone metastasis mediates resistance to androgen deprivation in tissue culture. Simultaneously, we have reported that BMP6 induced castration resistance in CaP cells via tumour-infiltrating macrophages. Therefore, our present study aims to investigate the mechanism of WNT5A and its interaction with macrophages on CRPC. Doxycycline inducible WNT5A overexpression prostate cancer cell line was used for detailed mechanical study. WNT5A was associated with increased expression of chemokine ligand 2 (CCL2) in the human CaP cell line, LNCaP. Mechanistically, this induction of CCL2 by WNT5A is likely to be mediated via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signalling pathway. Our in vivo experiments demonstrated that the overexpression of WNT5A in LNCaP cells promoted castration resistance. Conversely, this resistance was inhibited with the removal of macrophages via clodronate liposomes. When patient-derived CaP LuCaP xenografts were analysed, high levels of WNT5A were correlated with increased levels of CCL2 and BMP6. In addition, higher levels of CCL2 and BMP6 were more commonly observed in intra-femoral transplanted tumours as compared to subcutaneous-transplanted tumours in the patient-derived PCSD1 bone-niche model. These findings collectively suggest that WNT5A may be a key gene that induces CRPC in the bone niche by recruiting and regulating macrophages through CCL2 and BMP6, respectively.

In this study, we determined the effect of TNF-α on hBMSCs proliferation as well as the role of IL-1 receptor-associated kinase 1 (IRAK1) on TNF-α signaling. Western blot analysis revealed that TNF-α treatment increased the phosphorylation of IRAK1 in hBMSCs. The downregulation of IRAK1 inhibited TNF-α-induced NF-ĸB activation and COX-2 expression. TNF-α treatment increased hBMSCs proliferation in a dose-dependent manner and increased ERK, JNK, and NF-ĸB activity. U0126, an ERK inhibitor, decreased hBMSCs proliferation and significantly blocked TNF-α -induced hBMSCs proliferation. In cells with IRAK1 or TRADD downregulation, the U0126 treatment inhibited hBMSCs proliferation and significantly suppressed TNF-α-induced hBMSCs proliferation. The downregulation of IRAK1 or TRADD inhibited TNF-α-induced ERK and JNK activation, and hBMSCs proliferation. Inhibition of NF-ĸB by decoy oligonucleotides reduced the TNF-α-induced hBMSCs proliferation. Immunoprecipitation analysis showed that IRAK1 does not physically interact with TNF receptor 1 (TNFR1) even in the presence of TNF-α. Suppression of IRAK1 binding protein (IRAK1BP1) inhibited TNF-α-induced increase of the proliferation and ERK1 phosphorylation of hBMSCs in the presence of TNF-α. Our data indicate that TNF-α modulates hBMSCs proliferation through ERK signaling pathways, and that IRAK1 plays an important role in TNF-α-induced NF-ĸB activation in hBMSCs.

Oncological outcomes are improving in gastrointestinal cancer with advancements in systemic therapies, and there is notable potential in combining immunotherapy and radiation therapy (RT) to allow for further improvements. Various preclinical and early phase II studies have shown promising synergy with immunotherapy and RT in gastrointestinal cancer. A few recent phase III studies have shown improved survival with the addition of immunotherapy to standard treatment for gastrointestinal cancer. The timing, duration, sequencing, and integration with other anti-cancer treatments are still areas of ongoing research. We have reviewed the published and ongoing studies of the combinations of immunotherapy and RT in gastrointestinal cancers.

Kim J, et al. Korean J Radiol. 2023 Mar;24:e27. https://doi.org/10.3348/kjr.2023.0012