Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas

Abstract

Receptor activator of NF-kappaB ligand (RANKL) and its receptor, receptor activator of NF-kappaB (RANK), play a key role in osteoclastogenesis, and osteoprotegerin (OPG) acts as a decoy receptor for RANKL. We investigated the role of the RANKL-RANK-OPG system in renal cell carcinomas (RCCs), which frequently metastasize to bones. Real-time quantitative PCR revealed that RANKL mRNA expression was higher in clear cell RCCs than in papillary and chromophobe RCCs. Similarly, RANKL protein expression level in clear cell RCCs was higher than that in papillary and chromophobe RCCs, showing positive correlations with the primary tumour stage and distant metastasis. There was no significant association between the expression level of RANK, OPG and histological subtypes of RCC. RANKL and RANK expression was observed in metastatic RCCs in the bone and other organs, suggesting that they play a role in metastasis to the bone and other organs. Recombinant RANKL protein stimulated migration of a clear cell RCC cell line, Caki-1, in vitro, and this enhanced migration was inhibited by the administration of recombinant OPG protein. Furthermore, multivariate Cox analysis revealed that elevated RANKL and RANK expression with low-OPG expression was a significant and independent predictor of recurrence, bone metastasis and a poor prognosis. These data suggest that the RANKL-RANK-OPG system is involved not only in the bone metastasis of RCCs but also in metastasis to other organs through the stimulation of cancer cell migration.

C-Src-mediated RANKL-induced breast cancer cell migration by activation of the ERK and Akt pathway

“…RANKL interacts with RANK and, in turn, recruits tumor necrosis factor receptor-associated factors (TRAFs) (27), leading to the activation of NF-κB, c-Jun N-terminal kinase (JNK), p38, ERK and Akt (28)(29)(30). Recent studies (4,(12)(13)(14)(15) have shown that RANK is also expressed on the surface of certain cancer cells and that RANKL functions as a chemokine and directs RANK-expressing cancer cells to preferentially migrate into bone, which is the crucial and initial step for bone metastasis. However, the manner in which this cytokine is involved in tumor metastasis remains to be elucidated.…”

“…A number of studies have examined and confirmed the link between the RANK/RANKL pathway and propensity to metastasize to the bone (4,12,31). Recently, clinical trials with a fully human anti-RANKL antibody, denosumab, have been initiated in patients with prostate and breast cancer bone metastases with promising results (32,33).…”

“…Previous studies showed that RANKL binds to RANK or the decoy receptor osteoprotegrein (OPG) (5) to modulate osteoclast differentiation, activation and survival (6)(7)(8)(9)(10)(11). RANK is reportedly expressed in certain cancer cells, and the RANKL/RANK pathway induces the migration of prostate, renal, lung and human breast cancer cells, T47D (4,(12)(13)(14)(15). Furthermore, the RANKL/RANK pathway has been shown to trigger the bone-specific migration of RANK-expressing mouse malignant melanoma and human prostate cancer cells (4,13).…”

RANKL-induced migration of MDA-MB-231 human breast cancer cells via Src and MAPK activation

“…Interestingly, recent studies found that functional RANK was expressed in some primary and some secondary bone tumors, including osteosarcoma (5,6), chondrosarcoma (7), breast cancer (8), prostate cancer (9,10), renal cell cancer (11) and malignant melanoma (8). RANKL can promote cancer cell migration and invasion in in vitro experiments, and induce osteoclast chemotaxis (7,10,12).…”

Prognostic value of receptor activator of nuclear factor kappa-B (RANK) marker in patients with breast cancer

“…Сигнальный путь RANK / RANKL / OPG достаточно изучен в доклинических исследованиях, выработанная гипотеза об участии этих маркеров в образовании мета-стазов в костной ткани сподвигла ученых к их изучению в естественных условиях [19][20][21]. В клинических условиях нескольких исследований обнаружили связь между высо-ким уровнем RANK в первичной опухоли и склонностью к развитию костных метастазов [7,22].…”