Involvement of redox signalling in tumour cell dormancy and metastasis.

Decades of research on oncogene-driven carcinogenesis and gene-expression regulatory networks only started to unveil the complexity of tumour cellular and molecular biology. This knowledge has been successfully implemented in the clinical practice to treat primary tumours. In contrast, much less progress has been made in the development of new therapies against metastasis, which are the main cause of cancer-related deaths. More recently, the role of epigenetic and microenviromental factors has been shown to play a key role in tumour progression. Free radicals are known to communicate the intracellular and extracellular compartments, acting as second messengers and exerting a decisive modulatory effect on tumour cell signalling. Depending on the cellular and molecular context, as well as the intracellular concentration of free radicals and the activation status of the antioxidant system of the cell, the signalling equilibrium can be tilted either towards tumour cell survival and progression or cell death. In this regard, recent advances in tumour cell biology and metastasis indicate that redox signalling is at the base of many cell-intrinsic and microenvironmental mechanisms that control disseminated tumour cell fate and metastasis. In this manuscript, we will review the current knowledge about redox signalling along the different phases of the metastatic cascade, including tumour cell dormancy, making emphasis on metabolism and the establishment of supportive microenvironmental connections, from a redox perspective.

Targeted α Therapies for the Treatment of Bone Metastases.

The skeleton is the target tissue for many types of tumors, and, recently, the survival of patients with prostate cancer metastasis has been increased using α-emitting drugs known as targeted α therapies. The use of α-radiopharmaceuticals in medicine was hypothesized at the beginning of the nineteenth century after the observation that α-radionuclides were associated with high cell-killing energy and low tissue penetration in healthy tissues. In the prostate cancer (PC) scenario, current research suggests that this class of radiopharmaceuticals has limited toxicity, and that the mechanism of action does not overlap with pre-existing drugs, allowing us to extend therapeutic armaments and address medical oncology towards personalized and precision medicine. Ongoing studies may extend these benefits also to bone metastases deriving from other neoplasms. The aim of this review is to summarize the current research on targeted α therapies and try to identify the right patient to be treated in the right time in order to integrate in these medications in the every-day clinical practice.

Osteoblasts and osteoclasts: an important switch of tumour cell dormancy during bone metastasis.

Bone metastasis occurs when tumour cells dissociate from primary tumours, enter the circulation (circulating tumour cells, CTCs), and colonize sites in bone (disseminated tumour cells, DTCs). The bone marrow seems to be a particularly dormancy-inducing environment for DTCs, yet the mechanisms of dormancy initiation, reactivation, and interaction within the bone marrow have to be elucidated. Intriguingly, some evidence has suggested that dormancy is a reversible state that is switched 'on' or 'off' depending on the presence of various bone marrow resident cells, particularly osteoclasts and osteoblasts. It has become clear that these two cells contribute to regulating dormant tumour cells in bone both directly (interaction) and indirectly (secreted factors). The involved mechanisms include TGFß signalling, the Wnt signalling axis, the Notch2 pathway, etc. There is no detailed review that specifically focuses on ascertaining the dynamic interactions between tumour cell dormancy and bone remodelling. In addition, we highlighted the roles of inflammatory cytokines during this 'cell-to-cell' communication. We also discussed the potential clinical relevance of remodelling the bone marrow niche in controlling dormant tumour cells. Understanding the unique role of osteoclasts and osteoblasts in regulating tumour dormancy in bone marrow will provide new insight into preventing and treating tumour bone metastasis.

Intact LKB1 activity is required for survival of dormant ovarian cancer spheroids.

Metastatic epithelial ovarian cancer (EOC) cells can form multicellular spheroids while in suspension and disperse directly throughout the peritoneum to seed secondary lesions. There is growing evidence that EOC spheroids are key mediators of metastasis, and they use specific intracellular signalling pathways to control cancer cell growth and metabolism for increased survival. Our laboratory discovered that AKT signalling is reduced during spheroid formation leading to cellular quiescence and autophagy, and these may be defining features of tumour cell dormancy. To further define the phenotype of EOC spheroids, we have initiated studies of the Liver kinase B1 (LKB1)-5'-AMP-activated protein kinase (AMPK) pathway as a master controller of the metabolic stress response. We demonstrate that activity of AMPK and its upstream kinase LKB1 are increased in quiescent EOC spheroids as compared with proliferating adherent EOC cells. We also show elevated AMPK activity in spheroids isolated directly from patient ascites. Functional studies reveal that treatment with the AMP mimetic AICAR or allosteric AMPK activator A-769662 led to a cytostatic response in proliferative adherent ovarian cancer cells, but they fail to elicit an effect in spheroids. Targeted knockdown of STK11 by RNAi to reduce LKB1 expression led to reduced viability and increased sensitivity to carboplatin treatment in spheroids only, a phenomenon which was AMPK-independent. Thus, our results demonstrate a direct impact of altered LKB1-AMPK signalling function in EOC. In addition, this is the first evidence in cancer cells demonstrating a pro-survival function for LKB1, a kinase traditionally thought to act as a tumour suppressor.