Locally advanced and metastatic invasive bladder cancer (BC) has a poor prognosis, and no advanced therapies beyond cisplatin‐based combination chemotherapy have been developed. Therefore, it is an ...urgent issue to elucidate the underlying mechanisms of tumor progression and metastasis of invasive BC for the development of new therapeutic strategies. Here, we clarified a novel role of exosomes containing ErbB2 and CRK in a formation of premetastatic niches and subsequent metastases. CRK adaptors were overexpressed in invasive UM‐UC‐3 BC cells. In an orthotopic xenograft model, metastases to lung, liver, and bone of UM‐UC‐3 cells were completely abolished by CRK elimination. Mass spectrometry analysis identified that ErbB2 was contained in UM‐UC‐3‐derived exosomes in a CRK‐dependent manner; the exosomes significantly increased proliferation and invasion properties of low‐grade 5637 BC cells and HUVECs through FAK and PI3K/AKT signaling pathways. In athymic mice educated with UM‐UC‐3‐derived exosomes, i.v. implanted UM‐UC‐3 cells were trapped with surrounding PKH67‐labeled exosomes in lung and led to development of lung metastasis with disordered vascular proliferation. In contrast, exosomes derived from CRK‐depleted BC cells failed to induce these malignant features. Taken together, we showed that CRK adaptors elevated the expression of ErbB2/3 in BC cells, and these tyrosine kinase/adaptor units were transferred from host BC cells to metastatic recipient cells by exosomes, leading to vascular leakiness and proliferation and contributing to the formation of distant metastasis. Thus, CRK intervention with ErbB2/3 blockade might be a potent therapeutic strategy for patients with ErbB2 overexpressing advanced and metastatic BC.
CRK adaptors elevate the expression of ErbB2/3 in bladder cancer (BC) cells, and these tyrosine kinase/adaptor units are transferred from host BC cells to metastatic recipient cells by exosomes, leading to vascular leakiness and proliferation and contributing to the formation of distant metastasis. Thus, CRK intervention with ErbB2/3 blockade might be a potent therapeutic strategy for patients with ErbB2 overexpressing advanced and metastatic BC.
The role of lymphadenectomy has been controversial in urological malignancies. Urothelial carcinoma of the bladder and upper urinary tract has a high potential to spread through the lymphatic network ...compared with other malignancies, including renal cell carcinoma or prostate cancer. In urothelial carcinoma of the bladder, lymphadenectomy of pelvic nodes had been considered as the standard procedure when radical cystectomy was carried out. Recently, many investigators have examined the influence of its extent, and the majority of the studies have supported the beneficial role of extended lymphadenectomy in accurate staging or in improving patient survival. Although randomized controlled trials are required to establish a greater level of evidence, more urological surgeons have already noticed the necessity for extended lymphadenectomy in bladder cancer. In contrast to bladder cancer, there have been far fewer studies on urothelial carcinoma of the upper urinary tract. This might be because of the smaller number of the patients with urothelial carcinoma of the upper urinary tract and the lack of understanding of regional nodes. However, studies of lymph node mapping and the retrospective analyses with respect to the benefit of lymphadenectomy have been carried out in urothelial carcinoma of the upper urinary tract by some investigators, although the results are still controversial. However, the results from multi‐institutional studies by high volume centers have supported the beneficial role of lymphadenectomy in urothelial carcinoma of the upper urinary tract, as it has been proposed in bladder cancer. Thus, lymphadenectomy for urothelial carcinoma of the bladder and the upper urinary tract might have a potential role in staging and improving the oncological outcomes.
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