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Background: Tumour dormancy, a resistance mechanism employed by cancer cells, is a significant challenge in cancer treatment, contributing to minimal residual disease (MRD) and potential relapse. Despite its clinical importance, the mechanisms underlying tumour dormancy and MRD remain unclear. In this study, we employed two syngeneic murine models of myeloid leukemia and melanoma to investigate the genetic, epigenetic, transcriptomic and protein signatures associated with tumour dormancy. We used a multiomics approach to elucidate the molecular mechanisms driving MRD and identify potential therapeutic targets. Results: We conducted an in-depth omics analysis encompassing whole-exome sequencing (WES), copy number variation (CNV) analysis, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome and proteome investigations. WES analysis revealed a modest overlap of gene mutations between melanoma and leukemia dormancy models, with a significant number of mutated genes found exclusively in dormant cells. These exclusive genetic signatures suggest selective pressure during MRD, potentially conferring resistance to the microenvironment or therapies. CNV, histone marks and transcriptomic gene expression signatures combined with Gene Ontology (GO) enrichment analysis highlighted the potential functional roles of the mutated genes, providing insights into the pathways associated with MRD. In addition, we compared "murine MRD genes" profiles to the corresponding human disease through public datasets and highlighted common features according to disease progression. Proteomic analysis combined with multi-omics genetic investigations, revealed a dysregulated proteins signature in dormant cells with minimal genetic mechanism involvement. Pathway enrichment analysis revealed the metabolic, differentiation and cytoskeletal remodeling processes involved in MRD. Finally, we identified 11 common proteins differentially expressed in dormant cells from both pathologies. Conclusions: Our study underscores the complexity of tumour dormancy, implicating both genetic and nongenetic factors. By comparing genomic, transcriptomic, proteomic, and epigenomic datasets, our study provides a comprehensive understanding of the molecular landscape of minimal residual disease. These results provide a robust foundation for forthcoming investigations and offer potential avenues for the advancement of targeted MRD therapies in leukemia and melanoma patients, emphasizing the importance of considering both genetic and nongenetic factors in treatment strategies. [ABSTRACT FROM AUTHOR]

Abstract Background Tumour dormancy, a resistance mechanism employed by cancer cells, is a significant challenge in cancer treatment, contributing to minimal residual disease (MRD) and potential relapse. Despite its clinical importance, the mechanisms underlying tumour dormancy and MRD remain unclear. In this study, we employed two syngeneic murine models of myeloid leukemia and melanoma to investigate the genetic, epigenetic, transcriptomic and protein signatures associated with tumour dormancy. We used a multiomics approach to elucidate the molecular mechanisms driving MRD and identify potential therapeutic targets. Results We conducted an in-depth omics analysis encompassing whole-exome sequencing (WES), copy number variation (CNV) analysis, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome and proteome investigations. WES analysis revealed a modest overlap of gene mutations between melanoma and leukemia dormancy models, with a significant number of mutated genes found exclusively in dormant cells. These exclusive genetic signatures suggest selective pressure during MRD, potentially conferring resistance to the microenvironment or therapies. CNV, histone marks and transcriptomic gene expression signatures combined with Gene Ontology (GO) enrichment analysis highlighted the potential functional roles of the mutated genes, providing insights into the pathways associated with MRD. In addition, we compared “murine MRD genes” profiles to the corresponding human disease through public datasets and highlighted common features according to disease progression. Proteomic analysis combined with multi-omics genetic investigations, revealed a dysregulated proteins signature in dormant cells with minimal genetic mechanism involvement. Pathway enrichment analysis revealed the metabolic, differentiation and cytoskeletal remodeling processes involved in MRD. Finally, we identified 11 common proteins differentially expressed in dormant cells from both pathologies. Conclusions Our study underscores the complexity of tumour dormancy, implicating both genetic and nongenetic factors. By comparing genomic, transcriptomic, proteomic, and epigenomic datasets, our study provides a comprehensive understanding of the molecular landscape of minimal residual disease. These results provide a robust foundation for forthcoming investigations and offer potential avenues for the advancement of targeted MRD therapies in leukemia and melanoma patients, emphasizing the importance of considering both genetic and nongenetic factors in treatment strategies. Graphical Abstract

Recurrence of oestrogen receptor (ER)-positive breast cancer rarely occurs postoperatively after a long period. Breast cancer cells survive and settle in distant organs in a dormant state, a phenomenon known as “tumour dormancy.” Here, we present a 66-year-old woman with recurrence of ER-positive breast cancer in the left lung 23 years after surgery accompanied with non-tuberculous mycobacterium infection (NTM). At the age of 43 years, the patient underwent a right mastectomy and adjuvant hormonotherapy to completely cure breast cancer. Twenty-three years after the operation, when the patient was 66 years old, computed tomography presented nodular shadows in the lower lobes bilaterally with bronchiectasis and ill-defined satellite tree-in-bud nodules. Mycobacterium intracellulare was detected in cultured bronchoalveolar lavage fluid obtained from the left lower lobe by bronchoscopy. Rifampicin, ethambutol, and clarithromycin were started, which resulted in shrinkage of the nodule in the right lower lobe and satellite nodules; however, the nodule in the left lower lobe increased in size gradually. Wedge resection of the left lower lobe containing the nodule by video-assisted thoracoscopic surgery was performed, which demonstrated that the nodule was adenocarcinoma in intraoperative pathological diagnosis; therefore, a left lower lobectomy and mediastinal lymph node dissection were performed. The tumour was revealed to be consistent with recurrence of previous breast cancer according to its morphology and immunohistochemical staining. Furthermore, caseous epithelioid cell granulomas existed in the periphery of the tumour. It is reported that inflammatory cytokines induce reawakening of dormant oestrogen-dependent breast cancer and, in our case, NTM infection might have stimulated the dormant tumour cells in the lower lobe.

The connection between indoleamine 2,3-dioxygenase 1 (IDO1) and tumour dormancy – a quiescent state of tumour cells which has been consistently linked to metastasis and cancer recurrence – is rarely discussed despite the pivotal role of IDO1 in cancer development and progression. Whilst the underlying mechanisms of IDO1-mediated dormancy are elusive, we summarize the IDO1 pathways which potentially contribute to dormancy in this review. Critically, distinct IDO1 activities are involved in dormancy initiation and maintenance; factors outside the well-studied IDO1/kynurenine/aryl hydrocarbon receptor axis, including the mammalian target of rapamycin and general control nonderepressible 2, appear to be implicated in dormancy. We also discuss various strategies for cancer treatment via regulating IDO1-dependent dormancy and suggest the application of nanotechnology to deliver effective treatment. [ABSTRACT FROM AUTHOR]

The connection between indoleamine 2,3-dioxygenase 1 (IDO1) and tumour dormancy – a quiescent state of tumour cells which has been consistently linked to metastasis and cancer recurrence – is rarely discussed despite the pivotal role of IDO1 in cancer development and progression. Whilst the underlying mechanisms of IDO1-mediated dormancy are elusive, we summarize the IDO1 pathways which potentially contribute to dormancy in this review. Critically, distinct IDO1 activities are involved in dormancy initiation and maintenance; factors outside the well-studied IDO1/kynurenine/aryl hydrocarbon receptor axis, including the mammalian target of rapamycin and general control nonderepressible 2, appear to be implicated in dormancy. We also discuss various strategies for cancer treatment via regulating IDO1-dependent dormancy and suggest the application of nanotechnology to deliver effective treatment.

Cancer metastasis is a unique feature of malignant tumours. Even bone can become a common colonization site due to the tendency of solid tumours, including breast cancer (BCa) and prostate cancer (PCa), to metastasize to bone. Currently, a previous concept in tumour metabolism called tumour dormancy may be a promising target for antitumour treatment. When disseminated tumour cells (DTCs) metastasize to the bone microenvironment, they form a flexible regulatory network called the "bone-tumour-inflammation network". In this network, bone turnover as well as metabolism, tumour progression, angiogenesis and inflammatory responses are highly unified and coordinated, and a slight shift in this balance can result in the disruption of the microenvironment, uncontrolled inflammatory responses and excessive tumour growth. The purpose of this review is to highlight the regulatory effect of the "bone-tumour-inflammation network" in tumour dormancy. Osteoblast-secreted factors, bone turnover and macrophages are emphasized and occupy in the main part of the review. In addition, the prospective clinical application of tumour dormancy is also discussed, which shows the direction of future research. [ABSTRACT FROM AUTHOR]

Quiescence in cancer cells is considered a therapeutic challenge as it confers dormancy in tumour, hence circumventing inherent anti-neoplastic surveillance system and standard-of-care cancer therapeutics including chemotherapy and radiotherapy. Since majority of the therapeutics target actively proliferating cancer cells, cancer cells eventually develop quiescent nature as mechanism of survival and cancer progression under both niche and therapeutic pressures. Quiescence state in cancer cells, eventually, confers resistant and aggressive nature to conventional cancer therapies, resulting in disease progression and relapse. Therefore, targeting quiescent cancer cells or cancer stem cells is a promising therapeutic approach, however an extensive review of the relevant information is needed in order to device an effective therapy. While the evidence of quiescence regulation in CSCs is rather a complex molecular and cellular network, herein, we aim to provide a comprehensive understanding of both intrinsic and extrinsic regulation in association with the function of CSCs. Findings on induction of quiescent state in CSCs population, its regulation at both cellular and molecular level, key molecular regulators, cellular events and processes including potential targets to develop therapeutics are extensively reviewed. This review also highlights the impact of CSC plasticity on quiescence which capturing the key challenge of targeting the cells in this state. Beyond understanding the mechanisms underlying quiescence nature of cancer cells, this review provides insightful perspective and future direction on insight in targeting these populations, hence collapse the tumour dormancy programme in order to eradicate tumour mass as a whole. [ABSTRACT FROM AUTHOR]

Abstract Background The number of patients requesting autologous breast reconstruction (ABR) after mastectomy for breast cancer has increased over the past decades. However, concern has been expressed about the oncological safety of ABR. The aim of our study was to assess the effect of ABR on distant relapse. Methods In this retrospective cohort study, data was analysed from patients who underwent mastectomy for invasive breast cancer in University Hospitals Leuven between 2000 and 2011. In total, 2326 consecutive patients were included, 485 who underwent mastectomy with ABR and 1841 who underwent mastectomy alone. The risk of relapse in both groups was calculated using a Cox proportional hazards analysis, adjusted for established prognostic factors. ABR was considered as a time-dependent variable. Additionally, the evolution of the risk over follow-up time was calculated. Results With a median follow-up of 68 months, 8% of patients in the reconstruction group developed distant metastases compared to 15% in the mastectomy alone group (univariate HR 0.70, 95% CI 0.50–0.97, p = 0.0323). However, after adjustment for potential confounding factors in a Cox multivariable analysis, the risk of distant relapse was no longer significantly different between groups (multivariate HR 0.82, 95% CI 0.55–1.22, p = 0.3301). Moreover, the risk of metastasis after reconstruction was not time-dependent. Conclusions These findings suggest that there is no effect of ABR on distant relapse rate and thus that ABR is an oncological safe procedure. The rate of local recurrence was too low to make any significant conclusions.

Recurrence of oestrogen receptor (ER)-positive breast cancer rarely occurs postoperatively after a long period. Breast cancer cells survive and settle in distant organs in a dormant state, a phenomenon known as "tumour dormancy." Here, we present a 66-year-old woman with recurrence of ER-positive breast cancer in the left lung 23 years after surgery accompanied with non-tuberculous mycobacterium infection (NTM). At the age of 43 years, the patient underwent a right mastectomy and adjuvant hormonotherapy to completely cure breast cancer. Twenty-three years after the operation, when the patient was 66 years old, computed tomography presented nodular shadows in the lower lobes bilaterally with bronchiectasis and ill-defined satellite tree-in-bud nodules. Mycobacterium intracellulare was detected in cultured bronchoalveolar lavage fluid obtained from the left lower lobe by bronchoscopy. Rifampicin, ethambutol, and clarithromycin were started, which resulted in shrinkage of the nodule in the right lower lobe and satellite nodules; however, the nodule in the left lower lobe increased in size gradually. Wedge resection of the left lower lobe containing the nodule by video-assisted thoracoscopic surgery was performed, which demonstrated that the nodule was adenocarcinoma in intraoperative pathological diagnosis; therefore, a left lower lobectomy and mediastinal lymph node dissection were performed. The tumour was revealed to be consistent with recurrence of previous breast cancer according to its morphology and immunohistochemical staining. Furthermore, caseous epithelioid cell granulomas existed in the periphery of the tumour. It is reported that inflammatory cytokines induce reawakening of dormant oestrogen-dependent breast cancer and, in our case, NTM infection might have stimulated the dormant tumour cells in the lower lobe. [ABSTRACT FROM AUTHOR]

Bone metastases (BM) are a very common complication of the most prevalent human cancers. BM are extremely painful and may be life-threatening when associated with hypercalcaemia. BM can lead to kidney failure and cardiac arrhythmias and arrest, but why and how do cancer cells decide to “switch homes” and move to bone? In this review, we will present what answers science has provided so far, with focus on the molecular mechanisms and cellular aspects of well-established findings, such as the concept of “vicious cycle” and “osteolytic” vs. “osteosclerotic” bone metastases; as well as on novel concepts, such as cellular dormancy and extracellular vesicles. At the molecular level, we will focus on hypoxia-associated factors and angiogenesis, the Wnt pathway, parathyroid hormone-related peptide (PTHrP) and chemokines. At the supramolecular/cellular level, we will discuss tumour dormancy, id est the mechanisms through which a small contingent of tumour cells coming from the primary site may be kept dormant in the endosteal niche for many years. Finally, we will present a potential role for the multimolecular mediators known as extracellular vesicles in determining bone-tropism and establishing a premetastatic niche by influencing the bone microenvironment.

Background: The number of patients requesting autologous breast reconstruction (ABR) after mastectomy for breast cancer has increased over the past decades. However, concern has been expressed about the oncological safety of ABR. The aim of our study was to assess the effect of ABR on distant relapse.Methods: In this retrospective cohort study, data was analysed from patients who underwent mastectomy for invasive breast cancer in University Hospitals Leuven between 2000 and 2011. In total, 2326 consecutive patients were included, 485 who underwent mastectomy with ABR and 1841 who underwent mastectomy alone. The risk of relapse in both groups was calculated using a Cox proportional hazards analysis, adjusted for established prognostic factors. ABR was considered as a time-dependent variable. Additionally, the evolution of the risk over follow-up time was calculated.Results: With a median follow-up of 68 months, 8% of patients in the reconstruction group developed distant metastases compared to 15% in the mastectomy alone group (univariate HR 0.70, 95% CI 0.50-0.97, p = 0.0323). However, after adjustment for potential confounding factors in a Cox multivariable analysis, the risk of distant relapse was no longer significantly different between groups (multivariate HR 0.82, 95% CI 0.55-1.22, p = 0.3301). Moreover, the risk of metastasis after reconstruction was not time-dependent.Conclusions: These findings suggest that there is no effect of ABR on distant relapse rate and thus that ABR is an oncological safe procedure. The rate of local recurrence was too low to make any significant conclusions. [ABSTRACT FROM AUTHOR]

The main priority when designing cancer immuno-therapies has been to seek viable biological mechanisms that lead to permanent cancer eradication or cancer control. Understanding the delicate balance between the role of effector and memory cells on eliminating cancer cells remains an elusive problem in immunology. Here we make an initial investigation into this problem with the help of a mathematical model for oncolytic virotherapy; although the model can in fact be made general enough to be applied also to other immunological problems. According to this model, we find that long-term cancer control is associated with a large number of persistent effector cells (irrespective of the initial peak in effector cell numbers). However, this large number of persistent effector cells is sustained by a relatively large number of memory cells. Moreover, the results of the mathematical model suggest that cancer control from a dormant state cannot be predicted by the size of the memory population. [ABSTRACT FROM AUTHOR]

Complete surgical resection, accessible therapeutic targets and effective tyrosine kinase inhibitors (TKIs) have not completely cured gastrointestinal stromal tumours (GISTs), with most patients suffering from residual tumours and recurrence. The existence of nerve infiltration in GIST provides a way for tumour cells to escape local resection and systemic targeted therapy, which may challenge the previous understanding of its behaviour patterns and inspire the development of more radical excision and more precise targeted therapy. Moreover, tumour dormancy has emerged as a major cause of drug resistance and tumour relapse. Among these pathways, the nerve-tumour regulatory axis GDNF-GFRA1 is activated in GISTs, assists tumour cells in achieving dormancy and protects them from apoptosis under environmental stress by enhancing autophagic flux. The concrete mechanism is that the GDNF-regulating interaction between GFRA1 and the lysosomal calcium channel MCOLN1 activates Ca2+-dependent TFEB signalling. Activated TFEB transcriptionally regulates intracellular lysosome levels, which could achieve feedback upregulation of cellular autophagy flux during TKI treatment. This dormancy-transition axis fills parts of the mechanistic vacancy before the onset of secondary mutations, and strategies for TKIs combined with targeting GFRA1-dependent autophagy have distinct promise as prospective clinical therapies. [ABSTRACT FROM AUTHOR]

The dynamics of disease recurrence shows a bimodal pattern with a fairly broad dominant peak at about 1.5-2 years after surgery followed by a second peak at about 5 years. Nowadays, this clinical pattern is explained by assuming that primary breast tumours as well as their metastases have phases of both arrested (tumour dormancy) and active Gompertzian growth. Tumour dormancy at metastatic sites is currently ascribed to biological particularities of local tissue microenvironments that inhibit the growth of tumour cells. However, in some patients, tumour dormancy appears to also depend on the direct interplay between the primary tumour and those metastases, a biological phenomenon called 'concomitant resistance'. Concomitant resistance is related to three biological processes: concomitant immunity, tumour-induced angiogenesis and athrepsia. Concomitant resistance can explain the bimodal relapse pattern of breast cancer patients as well as many other clinical phenomena such as the better clinical outcome among patients surgically treated during the putative early luteal phase, or the worse clinical outcome of African-American premenopausal women. Any therapeutic interventions (even surgery) can affect concomitant resistance with the potential to induce a worse as well as a better clinical outcome. This should be taken into account when planning new treatment strategies. [ABSTRACT FROM AUTHOR]

The skeleton is a common site for the establishment of distant metastases. Once cancers occupy bone, the prognosis is poor as disease recurrence and visceral spread is imminent. Understanding the pathways and cellular interactions, which regulate tumour cell seeding, dormancy and growth in bone, is pertinent to improving outcomes for patients with advanced cancers. Advances in imaging techniques have facilitated the development of the concept that the behavior of bone marrow resident cells dictates the fate of tumour cells upon arrival in bone. This review summarises recent findings achieved through intravital imaging. It highlights the importance of developing both longitudinal static and acute dynamic data to develop our understanding of tumour cell engraftment, dormancy, activation and the subsequent establishment of metastases. We also describe how imaging techniques have developed our knowledge of the elements that make up the complex bone microenvironment which tumour cells interact with to survive and grow. We also discuss how through combining these imaging insights with single cell RNA sequencing data, we are entering a new era of research which has the power to define the cell-cell interactions which control tumour cell growth in bone. • Intravital imaging in bone has revealed exciting new insights into bone cell biology. • Single cell imaging provides new insight into the initiation of bone tumours. • Single cell RNA sequencing unravels complexities of the tumour-bone niche. [ABSTRACT FROM AUTHOR]

Breast cancer is now the most frequently diagnosed cancer and leading cause of cancer death in women worldwide. Strategies targeting the primary tumour have markedly improved, but systemic treatments to prevent metastasis are less effective; metastatic disease remains the underlying cause of death in the majority of patients with breast cancer who succumb to their disease. The long latency period between initial treatment and eventual recurrence in some patients suggests that a tumour may both alter and respond to the host systemic environment to facilitate and sustain disease progression. Results from studies in animal models suggest that specific subtypes of breast cancer may direct metastasis through recruitment and activation of haematopoietic cells. In this review, we focus on data implicating breast cancer as a systemic disease. [ABSTRACT FROM AUTHOR]

Abstract: Cancer stem cells (CSCs) represent a subpopulation of tumour cells endowed with self-renewal and multi-lineage differentiation capacity but also with an innate resistance to cytotoxic agents, a feature likely to pose major clinical challenges towards the complete eradication of minimal residual disease in cancer patients. Operationally, CSCs are defined by their tumour-propagating ability when serially transplanted into immune-compromised mice and by their capacity to fully recapitulate the original heterogeneity of cell types observed in the primary lesions they are derived from. CSCs were first identified in haematopoietic malignancies and later in a broad spectrum of solid tumours including those of the breast, colon and brain. Notably, several CSC characteristics are relevant to metastasis, such as motility, invasiveness and, as mentioned above, resistance to DNA damage-induced apoptosis. Here, we have reviewed the current literature on the relation between CSCs and metastasis formation. Preliminary studies on cancer cell lines and patient-derived material suggest a rate-limiting role for stem-like cells in the processes of tumour cell dissemination and metastasis formation. However, additional studies are needed to deliver formal proof of their identity as the cell of origin of recurrences at distant organ sites. Nevertheless, several studies have already provided pre-clinical evidence of the efficacy of novel therapies directed against disseminated CSCs. [Copyright &y& Elsevier]

The study of complex systems has clearly evidenced that a few overall behavioural properties cannot be inferred from the properties of their single parts and are rather determined by their architecture. Such an approach has been recently proposed in biology to understand genome functioning and in oncology to endeavour a more consistent explanation of the variegated cancer behaviours. In the present perspective, we summarise the basic concepts of the proposed global approach and then we reconsider, in this new context, tumour dormancy and primary tumour removal effects, which recently emerged as critical points for breast cancer understanding. [ABSTRACT FROM AUTHOR]

Multiple drug resistance (multidrug resistance; MDR), a phenomenon whereby human tumours that acquire resistance to one type of therapy are found to be resistant to several other drugs that are often quite different in both structure and mode of action, has been recognised clinically for several decades. An important advance in our understanding of MDR came with the identification of P-glycoprotein and other related transporters that were expressed in some cancer cells and could recognise and catalyse the efflux of diverse anticancer drugs from cells. A second advance came from an understanding of the mechanism of programmed cell death or apoptosis, leading to MDR mediated by increased to resistance to anticancer drug-induced apoptosis. A third advance came with the finding that the proliferation of human tumours was driven by a small population of self-renewing tumour cells, focussing attention on the MDR properties of these so-called tumour stem cells rather than on the cells that comprised the majority of the tumour population. A fourth advance was the delineation of features of the tumour microenvironment, including immunosuppression, which essentially provided tumour stem cells with an MDR phenotype. Most published work on the overcoming of MDR has concentrated on inhibition of drug transporters but the complexity of mechanisms contributing demands a broad strategy for the development of methods to overcome MDR in a clinical setting. [ABSTRACT FROM AUTHOR]

Purpose: To study whether ipsilateral breast tumour recurrence (IBTR) dynamics are modified by post-operative radiotherapy (RT). Methods and materials: The hazard rate for IBTR was analysed in a database from patients undergoing breast conserving surgery with or without post-operative radiotherapy within randomised clinical trials from the Milan Cancer Institute. Results: The hazard rate for IBTR presents a bimodal pattern. Post-operative radiotherapy, in addition to reducing IBTR incidence from 24.5% to 5.8% at 10 years, causes more than a one year delay in its clinical manifestation. Distant metastasis dynamics are not modified by radiotherapy administration. Conclusions: In the light of a biology-based model of breast cancer metastasis development, IBTR peak delay most likely originates in a more prolonged dormancy time that, in turn, is related to local microenvironment conditions. Present clinical findings suggest that, besides a direct killing effect on residual tumour cells, microenvironmental modifications may play a major role in RT effectiveness. [ABSTRACT FROM AUTHOR]

Background Ocular melanoma is easily treated by the removal of the eye or through plaque radiotherapy. However, after removal or control of the primary tumor, patients can develop fatal liver metastases up to 20 years later. It has been reported that difficulties in imaging single cells and the propensity for tumor cells to replicate rapidly in animal models account for the deficit of single-cell tumor dormancy models. Methods In this paper, we performed two animal experiments using green fluorescent-labeled uveal melanoma cells in nude mice. Cells were injected via tail-vein and the experiments ran 20 and 42 days, respectively. Labeled cells were imaged in vivo via skin-flap and epifluorescent microscopy. Results The first experiment exemplified the feasibility of a single-cell tumor dormancy model; cells were present in multiple organs post-injection, but persisted solely in the liver for the duration of the experiment. The second experiment, demonstrating the presence and viability of these single, metastatic seeds 6 weeks after injection. Conclusion Due to the inherent difficulties in establishing single-celled tumor dormancy models, few exist. In this paper, we have successfully developed a single-cell dormancy model of uveal melanoma, a disease that, in patients, epitomizes tumor dormancy. This model has the potential to reveal the mechanisms behind dormancy, identify patients at high risk for metastatic development, and develop new serum biomarkers for micrometastasis detection. [ABSTRACT FROM AUTHOR]

Many epithelial cancers carry a poor prognosis even after curative resection of early stage tumours. Tumour progression in these cancer patients has been attributed to the existence and persistence of disseminated tumour cells (DTC) in various body compartments as a sign of minimal residual disease. Bone marrow (BM) has been shown to be a common homing organ and reservoir for DTC. A significant correlation between the presence of DTC in BM and metastatic relapse has been reported in various tumour types. However, only a portion of patients with DTC in BM at primary surgery relapse. Thus far, little is known about the conditions required for the persistence of dormancy or the escape from the dormant phase into the active phase of metastasis formation. Thereby, this peculiar stage of conceivably balanced tumour cell division and death may last for decades in cancer patients. Most likely, the ability of a dormant DTC to “be activated” is a complex process involving (i) somatic aberrations in the tumour cells, (ii) the interaction of the DTC with the new microenvironment at the secondary site, and (iii) hereditary components of the host (i.e., cancer patient). In this review, we will summarize the key findings of research on micrometastatic cancer cells and discuss these findings in the context of the concept of tumour dormancy. [ABSTRACT FROM AUTHOR]

The inability of tumour-initiating cancer stem cells (CSCs) to bring about a net increase in tumour mass could be described as a source of tumour dormancy. While CSCs may be intrinsically capable of driving malignant growth, to do so they require compatible surroundings of supportive cells, growth factors, adhesion molecules and energy sources (e.g. glucose and oxygen), all of which constitute what may be referred to as a ‘permissive' CSC niche. However, in some circumstances, the configuration of these factors could be incompatible with CSC growth (a ‘non-permissive' niche) and lead to their death or dormancy. CSCs and their niches may also differ between adult and paediatric cancers. In this regard the various facets of the tumour-vascular interface could serve as elements of the CSC niche. Indeed, transformed cells with an increased tumour-initiating capability may preferentially reside in specific zones adjacent to tumour blood vessels, or alternatively originate from poorly perfused and hypoxic areas, to which they have adapted. CSCs themselves may produce increased amounts of angiogenic factors, or rely for this on their progeny or activated host stromal cells. It is likely that ‘vascular' properties of tumour-initiating cells and those of their niches may diversify and evolve with tumour progression. The emerging themes in this area include the role of vascular (and bone marrow) aging, vascular and metabolic comorbidities (e.g. atherosclerosis) and the effects of the coagulation system (both at the local and systemic levels), all of which could impact the functionality of CSCs and their niches and affect tumour growth, dormancy and formation of occult as well as overt metastases. In this article we will discuss some of the vascular properties of CSCs relevant to tumour dormancy and progression, including: (i) the role of CSCs in regulating tumour vascular supply, i.e the onset and maintenance of tumour angiogenesis; (ii) the consequences of changing vascular demand (vascular dependence) of CSC and their progeny; (iii) the interplay between CSCs and the vascular system during the process of metastasis, and especially (iv) the impact of the coagulation system on the properties of CSC and their niches. We will use the oncogene-driven expression of tissue factor (TF) in cancer cells as a paradigm in this regard, as TF represents a common denominator of several vascular processes that commonly occur in cancer, most notably coagulation and angiogenesis. In so doing we will explore the therapeutic implications of targeting TF and the coagulation system to modulate the dynamics of tumour growth and tumour dormancy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Breast cancer is known for its propensity to recur even after decades. The biology behind this phenomenon of tumor dormancy is poorly understood. The stanniocalcins (stanniocalcin-1, STC-1 and stanniocalcin-2, STC-2) are 56kDa homodimeric proteins. They act as pro-survival factors and contribute to the endurance of terminally differentiated cells such as neurons and adipocytes. We investigated whether elevated expression of stanniocalcins also plays a part in the tumor dormancy of breast cancer. Methods: The expression of STC-1, STC-2 and estrogen receptor (ER) was studied by immunohistochemistry in 72 primary breast cancers and in their metastatic relapses detected before two years, or after 5 or 10 years from primary surgery. Results: When compared to primary tumors with early relapse and their metastases, the expression of STC-1 and STC-2 was significantly higher in relapses occurring after five year (STC-1 p =0.0012, STC-2 p =0.004) and even higher in very late relapses occurring 10 years after surgery (STC-1 p =0.0017, STC-2 p =0.0001). Moreover, primary tumors with a propensity of very late relapse displayed a higher initial expression of STC-2 (p =0.0001). A significantly increased frequency of ER expression was found in the very late relapses. Conclusion: These findings suggest that elevated expression of STC-1 or STC-2 act as survival factors also for breast cancer cells and thereby contribute to tumor dormancy. [Copyright &y& Elsevier]

LacZ (Gal)-reactive immune cells were transferred into athymic nu/ nu mice inoculated with Gal-expressing syngeneic tumour cells (ESbL-Gal) in order to study tumour-protective T-cell memory. This transfer prevented tumour outgrowth in recipients and resulted in the persistence of a high frequency of Gal-specific CD8+ T cells in the bone marrow and spleen. In contrast, such Ag-specific memory CD8+ T cells were not detectable by peptide–major histocompatibility complex (MHC) multimer staining in animals that had not previously received an antigenic challenge. Even though CD44hi memory T cells from the bone marrow showed a significantly higher turnover rate, as judged by bromodeoxyuridine (BrdU) incorporation, than respective cells from spleen or lymph nodes, as well as in comparison to CD44lo naïve T cells, these findings suggest that tumour-associated antigen (TAA) from residual dormant tumour cells are implicated in maintaining high frequencies of long-term surviving Gal-specific memory CD8+ T cells. Memory T cells could be recruited to the peritoneal cavity by tumour vaccination of immunoprotected nu/ nu mice and exhibited ex vivo antitumour reactivity. Long-term immune memory and tumour protection could be maintained over four successive transfers between tumour-inoculated recipients, which involved periodic antigenic restimulation in vivo prior to reisolating the cells for adoptive transfer. Using a cell line (ESbL-Gal-BM) that was established from dormant tumour cells isolated from the bone marrow of immunoprotected animals, it could be demonstrated that the tumour cells had up-regulated the expression of MHC class I molecules and down-regulated the expression of several adhesion molecules during the in vivo passage. Our results suggest that the bone marrow microenvironment has special features that are of importance for the maintenance of tumour dormancy and immunological T-cell memory, and that a low level of persisting antigen favours the maintenance of Ag-specific memory T cells over irrelevant memory T cells. [ABSTRACT FROM AUTHOR]

Objective To investigate the differentiation of embryonal carcinoma (EC) by cisplatin, and the underlying mechanism, as untreated metastases of nonseminomatous germ cell tumours rarely consist of fully differentiated mature somatic tissues, but such mature metastases are more common after various treatments, including chemotherapy. Materials and methods The TTSC-3 human testicular EC line heterotransplanted into nude mice was used as a target. After treating tumour-bearing mice with intraperitoneal injections of varying doses of cisplatin, the histopathology of the tumours was assessed and various gene expressions in the tumours determined by cDNA-array technology. Results When cisplatin at 1 mg/kg/week was injected intraperitoneally into TTSC-3-bearing mice, there was no effect on tumour growth. However, injecting cisplatin at 5 mg/kg/week induced a marked regression of the tumour. In contrast, cisplatin at 3 mg/kg/week had a modest inhibitory effect on tumour growth and induced tumour dormancy. Histological examination showed that 5 weeks after injecting cisplatin (3 mg/kg/week), primitive mesenchymal-like cells increased, and 10 weeks afterward cartilage and well-developed glands (teratoma) were apparent; at > 15 weeks afterward there were no EC cells visible. cDNA probes from reverse-transcribed mRNAs of TTSC-3 treated with cisplatin or saline for 10 weeks were compared to identify genes differentially expressed in cisplatin-treated TTSC-3. Of 1176 different human cDNA transcripts in cisplatin-treated TTSC-3, three genes (tumour necrosis factor receptor 1, caspase 8 and Apaf1 ), which are associated with apoptosis, were expressed markedly more than after saline injection. Conclusions The intermediate dose of cisplatin inhibited tumour growth of EC by inducing differentiation and enhancing apoptosis-related gene expression. These findings suggest that cisplatin may play a significant role in the differentiation of EC in vivo . [ABSTRACT FROM AUTHOR]

Bone metastasis is an uncommon event in advanced gastric cancer patients and bone metastases are rarely detected as isolated lesions. However, eleven years after treatment for locally advanced gastric cancer, including total gastrectomy followed by adjuvant chemotherapy, a 49-year-old female was admitted to the IX Division of General Surgery of the Second University of Naples (Naples, Italy) exhibiting severe progressive neurological symptoms. Magnetic resonance imaging indicated vertebral abnormalities, with evidence of marrow infiltration in several vertebral bodies; however, a contrast-enhanced computed tomography scan did not detect disease progression to other sites. Biopsy of the soft tissue at the level of the second lumbar vertebra (L2) revealed a metastatic lesion derived from gastric mucinous adenocarcinoma. The patient was initially treated with radiotherapy directed to the L2-L4 vertebral bodies to control the pain. Subsequently, systemic chemotherapy according to a FOLFOX-4 (leucovorin, fluorouracil and oxaliplatin) regimen commenced. However, after eight cycles, pulmonary progression of the disease occurred. Thus, palliative care was administered and the patient succumbed one month later. The late relapse of gastric cancer in the current patient may be associated with the theory of tumour dormancy. [ABSTRACT FROM AUTHOR]

Bone metastases (BM) are a very common complication of the most prevalent human cancers. BM are extremely painful and may be life-threatening when associated with hypercalcaemia. BM can lead to kidney failure and cardiac arrhythmias and arrest, but why and how do cancer cells decide to "switch homes" and move to bone? In this review, we will present what answers science has provided so far, with focus on the molecular mechanisms and cellular aspects of well-established findings, such as the concept of "vicious cycle" and "osteolytic" vs. "osteosclerotic" bone metastases; as well as on novel concepts, such as cellular dormancy and extracellular vesicles. At the molecular level, we will focus on hypoxia-associated factors and angiogenesis, the Wnt pathway, parathyroid hormone-related peptide (PTHrP) and chemokines. At the supramolecular/cellular level, we will discuss tumour dormancy, id est the mechanisms through which a small contingent of tumour cells coming from the primary site may be kept dormant in the endosteal niche for many years. Finally, we will present a potential role for the multimolecular mediators known as extracellular vesicles in determining bone-tropism and establishing a premetastatic niche by influencing the bone microenvironment. [ABSTRACT FROM AUTHOR]

Tumour dormancy presents challenges for clinical control and opportunities for scientific discovery. Current pictures of the mechanisms of tumour dormancy and reawakening remain incomplete. The Cancer Research UK's third Marshall Symposium explored tumour dormancy and reawakening in all their forms. In this forum article, we highlight the key challenges and opportunities discussed at this symposium., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)