癌细胞与骨微环境相互作用促进前列腺癌骨转移

骨转移是前列腺癌患者死亡的主要原因,目前尚无有效的治疗方法。由于骨微环境在此过程中起着重要作用,因此我们关注于癌细胞与骨微环境(包括破骨细胞、成骨细胞和骨基质细胞)之间的相互作用上。本文解释了前列腺癌细胞与骨微环境中转移相关细胞相互作用的机制,并进一步探讨了前列腺癌骨转移靶向治疗的最新进展。本文总结了骨微环境对前列腺癌转移的影响及其相关机制,为今后的前列腺癌转移研究提供新思路。     

前列腺癌骨转移后骨破坏相关信号通路的研究进展

骨转移是晚期前列腺癌患者常见的并发症之一,骨转移导致的疼痛等骨相关事件(SRE)治疗效果欠佳,预后差,严重影响患者的生命质量。因此,探究前列腺癌骨转移具有重要意义。目前,骨转移的相关机制尚不清楚,宿主微环境和前列腺癌细胞之间相互作用,形成恶性循环是一个重要原因。其中,RANK-RANKL信号通路的研究较为成熟。文章就前列腺癌骨转移相关信号通路的研究现状作一综述,并阐述同一信号分子在不同信号通路中的调控关系。     

前列腺癌骨转移机制和骨靶向药物研究进展

骨是前列腺癌最常见的晚期转移部位，骨微环境和前列腺癌中多种细胞因子如核因子-κB受体活化因子配体(Receptor activator of NF-κB ligand, RANKL)、趋化因子家族、整合素等通过复杂的相互作用机制参与了前列腺癌骨转移。多种骨靶向药物如二磷酸盐、地诺单抗和放疗药物如镭-223被批准用于预防和治疗因前列腺癌骨转移引起的骨骼相关事件(Skeletal-related events, SREs)。本文对前列腺癌骨转移的生物学机制和骨靶向药物研究进展进行综述。     

NF-κB通过调节GM-CSF促进乳腺癌的溶骨性骨转移

骨骼转移是乳腺癌最常见的并发症，也是造成晚期患者高病死率的主要原因。与前列腺癌骨转移灶以病理性骨增生为主不同，乳腺癌的骨转移呈现一个溶骨的特征。其中破骨细胞和肿瘤细胞之间存在的一个相互促进的恶性循环，被认为是导致溶骨主要作用环节，但是具体的分子机制一直不明。[第一段]     

恶性肿瘤骨转移分子机制的研究进展

骨转移是乳腺癌、前列腺癌等晚期恶性肿瘤的常见并发症。癌细胞增殖转移到骨引起溶骨性和成骨性骨损伤,其发生是多个因素共同作用的结果。近年来的研究发现肿瘤细胞与骨微环境之间存在相互作用,骨基质中富含的某些细胞因子如转化生长因子(TGFβ)、胰岛素样生长因子(IGFⅠ和IGFⅡ)等直接促进肿瘤细胞生长,并在维持骨形成和骨破坏的动态平衡中发挥重要作用。骨微环境中的物理因素包括缺氧、高钙、酸中毒等也为肿瘤生长提供适宜的条件。本文主要从分子水平阐述肿瘤骨转移过程中涉及到的肿瘤细胞与骨微环境之间的相互作用。     

前列腺癌的骨转移机制

前列腺癌骨转移的分子与细胞机制仍不清楚.前列腺癌骨转移过程中肿瘤细胞的趋化性,肿瘤细胞与骨骼微环境之间各种分子的相互作用以及肿瘤细胞、破骨细胞、成骨细胞和骨基质之间的恶性循环是近年来前列腺癌骨转移研究的热点.     

骨形成蛋白与前列腺癌

前列腺癌是西方国家男性最常见的恶性肿瘤之一,目前我国前列腺癌的发病率亦明显增加。前列腺和前列腺癌组织中有骨形成蛋白(bone morphogenetic proteins,BMPs)及其受体的表达。BMPs能够诱导异位成骨、细胞趋化、分化和胚胎发育。某些BMPs及其受体在前列腺癌细胞表达,可以作为前列腺癌发生、发展和预后的标志物。BMPs对前列腺癌细胞生物学行为的调控作用是多样的,与肿瘤细胞类型、分化状态和局部微环境有关。BMPs在前列腺癌进展过程中,特别是在促进前列腺癌骨转移并在成骨反应中发挥重要作用。研究BMPs与前列腺癌的关系,有助于阐明前列腺癌的发病及转移机制,为前列腺癌的治疗提供实验依据。     

乳腺癌骨转移机制与靶向治疗进展

乳腺癌骨转移是晚期乳腺癌常见的症状,乳腺癌细胞通过局部浸润、渗入血管和或淋巴管、随循环系统转移到骨、移出血管和或淋巴管、在骨定居并增殖引起溶骨性骨损伤。乳腺癌骨转移的发生发展取决于乳腺癌细胞与骨局部微环境之间相互作用,最后形成骨的结构破坏及功能受损。本文主要从分子水平阐述乳腺癌骨转移机制,并且综述针对乳腺癌骨转移关键靶点的抗骨转移药物的临床应用。     

驱动基因在肺癌骨转移中的研究进展

骨是肺癌常见的血行转移部位之一，其发生率为30%~40%，好发于脊柱和躯干近端，包括脊柱、股骨、肋骨和胸骨等。肺癌骨转移患者中位生存期为6~10月，治疗后1年生存率为40%~50%。骨转移分子机制的研究对治疗具有重要的指导意义。研究显示肺癌原发灶和骨转移灶驱动基因表达存在异质性，然而肺癌驱动基因在肺癌骨转移中的作用以及对骨微环境的的影响机制尚不明确。本文就肺癌骨转移分子机制研究进展进行综述，着重对常见肺癌驱动基因在肺癌骨转移中的作用及对骨微环境的影响进行阐述。     

恶性肿瘤骨转移机制探讨

骨骼是肿瘤最常见的转移部位,大约占1/3。尸解显示大约60％癌肿骨转移,80％以上骨转移癌是由乳腺癌、前列腺癌、肺癌、甲状腺癌和肾癌转移的,其中乳腺癌和前列腺癌转移率高达84％。骨转移中脊椎最常累及,其次为肋骨、骨盆和长干骨近端、胸骨和颅骨。脊柱转移主要发生在椎体,腰椎最好发,其次为胸椎,颈椎和骶椎。乳腺癌和肺癌常转移到胸椎,前列腺癌常侵犯腰椎、骶椎和骨盆。 恶性肿瘤可通过局部扩散或血液播散转移到骨,其中局部扩散非常少见,仅发生在口腔或鼻咽部癌肿侵入局部骨骼,或乳腺癌、肺癌或食管癌转移到胸骨。血液播散是癌肿转移到骨的主要途径;机制可能包括血管解剖特征,骨组织和肿瘤细胞的特性。 Ewing最早提出解剖定位理论(anatomically Or-     

The central role of osteoblasts in the metastasis of prostate cancer

Prostate cancer (PCa) is the most common malignancy in men. Although mortality from PCa has been declining over the past decade, metastasis can substantially shorten survival time and remains a major challenge in maintaining quality of life for survivors. PCa cells preferentially metastasize to bone and typically result in osteoblastic lesions. In the late stages of disease, however, osteolytic lesions are observed. The mechanisms of PCa bone metastasis are still unclear, but relationships between the PCa cells and the bone tissue elements are suspected of being more complex than initially thought. Far from being an innocent bystander, the bone participates actively in the metastatic process and provides the cancer cells with growth factors and a fertile environment. Among the various cells in the bone environment, osteoblasts have a central role through their bidirectional interactions with the PCa cells. This review discusses the possible mechanisms of PCa bone metastasis and highlights the essential role of osteoblasts in the metastasis of PCa to bone.     

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

The tendency of prostate cancer to produce osteoblastic bone metastases suggests that cancer cells and osteoblasts interact in ways that contribute to cancer progression. To identify factors that mediate these interactions, we compared gene expression patterns between two bone-derived prostate cancer cell lines that produce osteoblastic (MDA PCa 2b) or osteolytic lesions (PC-3). Both cell lines expressed Wnt ligands, including WNT7b, a canonical Wnt implicated in osteogenesis. PC-3 cells expressed 50 times more Dickkopf-1 (DKK1), an inhibitor of Wnt pathways, than did MDA PCa 2b cells. Evaluation of the functional role of these factors (in cocultures of prostate cancer cells with primary mouse osteoblasts (PMOs) or in bone organ cultures) showed that MDA PCa 2b cells activated Wnt canonical signaling in PMOs and that DKK1 blocked osteoblast proliferation and new bone formation induced by MDA PCa 2b cells. MDA PCa 2b cells did not induce bone formation in calvaria from mice lacking the Wnt co-receptor Lrp5. In human specimens, WNT7b was not expressed in normal prostate but was expressed in areas of high-grade prostate intraepithelial neoplasia, in three of nine primary prostate tumor specimens and in 16 of 38 samples of bone metastases from prostate cancer. DKK1 was not expressed in normal or cancerous tissue but was expressed in two of three specimens of osteolytic bone metastases (P=0.0119). We conclude that MDA PCa 2b induces new bone formation through Wnt canonical signaling, that LRP5 mediates this effect, and that DKK1 is involved in the balance between bone formation and resorption that determines lesion phenotype.     

Tumor expressed PTHrP facilitates prostate cancer-induced osteoblastic lesions

Expression of parathyroid hormone-related protein (PTHrP) correlates with prostate cancer skeletal progression; however, the impact of prostate cancer-derived PTHrP on the microenvironment and osteoblastic lesions in skeletal metastasis has not been completely elucidated. In this study, PTHrP overexpressing prostate cancer clones were stably established by transfection of full length rat PTHrP cDNA. Expression and secretion of PTHrP were verified by western blotting and IRMA assay. PTHrP overexpressing prostate cancer cells had higher growth rates in vitro, and generated larger tumors when inoculated subcutaneously into athymic mice. The impact of tumor-derived PTHrP on bone was investigated using a vossicle co-implant model. Histology revealed increased bone mass adjacent to PTHrP overexpressing tumor foci, with increased osteoblastogenesis, osteoclastogenesis and angiogenesis. In vitro analysis demonstrated pro-osteoclastic and pro-osteoblastic effects of PTHrP. PTHrP enhanced proliferation of bone marrow stromal cells and early osteoblast differentiation. PTHrP exerted a pro-angiogenic effect indirectly, as it increased angiogenesis but only in the presence of bone marrow stromal cells. These data suggest PTHrP plays a role in tumorigenesis in prostate cancer, and that PTHrP is a key mediator for communication and interactions between prostate cancer and the bone microenvironment. Prostate cancer-derived PTHrP is actively involved in osteoblastic skeletal progression.     

Prostate carcinoma skeletal metastases: cross-talk between tumor and bone

The majority of men with progressive prostate cancer develop metastases with the skeleton being the most prevalent metastatic site. Unlike many other tumors that metastasize to bone and form osteolytic lesions, prostate carcinomas form osteoblastic lesions. However, histological evaluation of these lesions reveals the presence of underlying osteoclastic activity. These lesions are painful, resulting in diminished quality of life of the patient. There is emerging evidence that prostate carcinomas establish and thrive in the skeleton due to cross-talk between the bone microenvironment and tumor cells. Bone provides chemotactic factors, adhesion factors, and growth factors that allow the prostate carcinoma cells to target and proliferate in the skeleton. The prostate carcinoma cells reciprocate through production of osteoblastic and osteolytic factors that modulate bone remodeling. The prostate carcinoma-induced osteolysis promotes release of the many growth factors within the bone extracellular matrix thus further enhancing the progression of the metastases. This review focuses on the interaction between the bone and the prostate carcinoma cells that allow for development and progression of prostate carcinoma skeletal metastases.     

Pourquoi certains cancers métastasent-ils préférentiellement à l’os ?

Bone metastases are common complications of several cancers, among which breast and prostate cancer are the most osteotropic. Different factors produced by the bone microenvironment draw cancer cells to invade the bone marrow where they seed in specific regions termed the premetastatic niche and the osteoblastic niche. Cancer cells then acquire bone-like properties to adapt and thrive in the bone microenvironment (osteomimicry). The inhibition of these mechanisms may offer new therapeutic perspectives, preventing bone metastasis formation inpatients at high risk of relapse in bone.     

Current trials using bone-targeting agents in prostate cancer

Prostate cancer metastasis is a unique disease. The propensity of prostate cancer to metastasize to bone and the prognostic significance of bone metastasis suggest that effective treatment of bone metastasis may provide clinical benefits. Both osteoblasts and osteoclasts have been shown to play a central role in the interactions between the metastatic prostate cancer cells and bone. Although most prostate cancer bone metastasis is osteoblastic, it remains unclear which cell type is initially involved in the process. Other components in the bone, such as the endothelium and stroma, may also play important roles in this process. The osteoblastic feature of prostate cancer bone metastasis has led to therapies focused on targeting osteoblast activity. Clinical trials targeting osteoblasts use radiopharmaceuticals (strontium-89 and samarium-153), the endothelin A receptor inhibitor atrasentan, or the vitamin D analog calcitriol. Agents that target osteoclasts include bisphosphonates; those that target endothelial cells include thalidomide and bevacizumab. Although these clinical trials for bone metastasis may provide effective treatments, novel concepts of how prostate cancer cells selectively metastasize to bone may advance our understanding and provide improved treatments for this difficult clinical problem. We propose a refined "seed" and "soil" view of metastasis. We speculate that in prostate cancer bone metastasis, the seed may comprise the so-called cancer stem cells, whereas the soil may comprise an onco-niche, ie, a unique microenvironment, that facilitate the growth and survival of cancer stem cells. If so, targeting cancer stem cells or the onco-niche may offer another way to improve treatment of prostate cancer bone metastasis.     

Placental bone morphogenetic protein (PLAB) gene expression in normal, pre-malignant and malignant human prostate: relation to tumor development and progression

The second most common target of prostate-cancer metastasis is bone, and the phenomenon of skeletal metastasis represents the incurable stage of disease. Histologically, skeletal metastasis from prostate cancer is distinctive due to its osteoblastic nature. The osteoblastic bone metastasis shows extensive new bone formation, with possible involvement of the soluble growth factors secreted by tumor cells, such as bone morphogenetic proteins (BMPs). In the present study, we analyzed the gene expression of one of the new members of the BMP family, placental bone morphogenetic protein (PLAB). In situ hybridization studies showed high levels of this gene in normal prostate. However, the gene is down-regulated during the progression of cancer at the primary site. The most significant finding was re-expression of the PLAB gene in osseous metastatic lesions. Our results demonstrate that tumor cells, when released from the primary site and after re-growth elsewhere, are capable of re-expressing specific genes that may play a different role at metastatic sites than at the primary site.     

The bisphosphonate YM529 inhibits osteolytic and osteoblastic changes and CXCR-4-induced invasion in prostate cancer

Bisphosphonates are useful for the treatment of prostate cancer bone metastasis. However, the role of bisphosphonate on the development of the osteoblastic component of prostate cancer bone metastases is not defined. In the present study, the third-generation bisphosphonate, YM529 (minodoronate), was tested for its effects on the osteolytic PC-3 and novel osteoblastic LNCaP-SF cell lines. YM529 inhibited both osteolytic and osteoblastic changes in an intratibial tumor injection murine model. In vitro, YM529 inhibited both the proliferation and the invasion of both prostate cancer cell lines. The stromal cell-derived factor-1 (or CXCL12)/CXCR-4 pathway is believed to play an important role in the development of prostate cancer bone metastases. Thus, we determined if YM529 affected this pathway. YM529 suppressed CXCR-4 expression in PC-3 and LNCaP-SF in vitro and in vivo and this was associated with decreased in vitro invasion. These results suggest that YM529 may inhibit cancer cell invasion into the bone matrix by repressing the expression of CXCR-4 in bone metastasis lesions.