Tumor Dormancy: Implications for Invasion and Metastasis

Gomatou, Georgia; Syrigos, Nikolaos; Vathiotis, Ioannis; Κοττέας, Ηλίας

doi:10.3390/ijms22094862

Cited by 36 publications

(19 citation statements)

References 123 publications

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“…Tumour cell dormancy is an intricate mechanism involving different molecular pathways and cell-cell interactions in accordance with the type of cancer and the microenvironmental signalling [ 32 ]. In our previous work we demonstrated that dormant BrCa cells interact with a specific osteoblast subpopulation, known as spindle-shaped N-Cadherin High osteoblasts (SNOs), remaining cell cycle arrested due to the Notch2 pathway.…”

Section: Discussionmentioning

confidence: 99%

Role of Neural (N)-Cadherin in Breast Cancer Cell Stemness and Dormancy in the Bone Microenvironment

Maurizi

Ciocca

Giuliani

et al. 2022

Cancers

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Breast cancer cells that interact with spindle-shaped N-Cadherin+ Osteoblasts (SNOs) are recognised to become dormant through a Notch2-dependent mechanism. We found that Notch2High human BrCa MDA-MB231 (MDA) cells also expressed high level of N-Cadherin. This prompted us to hypothesize that N-Cadherin could have a role in MDA-SNO interaction. Of note, the expression of N-Cadherin in MDA cells reduced tumour incidence and bone osteolysis in BrCa mouse model. Moreover, similarly to Notch2High MDA cells, the N-CadherinHigh MDA cells revealed a high expression of the canonical Haematopoietic Stem cell (HSC) markers, suggesting an HSC mimicry, associated with higher ability to form mammospheres. Interestingly, N-CadherinHigh MDA cells showed greater capacity to adhere to SNOs, while the inhibition of SNO-mediating MDA cell proliferation was unremarkable. To investigate whether these features were shared by mouse BrCa, we used the 4T1 cell line in which N-Cadherin expression was abolished and then rescued. At variance with MDA cells, 4T1 cells expressing N-Cadherin revealed that the latter was associated with a lower expression of the HSC marker, Cxcr4, along with a lower capacity to form mammospheres. Furthermore, the rescue of N-Cadherin expression increased cell-cell adhesion and reduced proliferation of 4T1 cells when they were co-plated with SNOs. In conclusion, we demonstrated that: (i) N-CadherinHigh and Notch2High MDA cells showed similar HSC mimicry and dormancy features; (ii) N-Cadherin mediated BrCa-SNO adhesion; (iii) N-Cadherin had a positive Notch2-dependent role on SNO-induced dormancy and HSC mimicry in MDA cells, and a negative role in 4T1 cell stemness and HSC mimicry.

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Section: Discussionmentioning

confidence: 99%

Role of Neural (N)-Cadherin in Breast Cancer Cell Stemness and Dormancy in the Bone Microenvironment

Maurizi

Ciocca

Giuliani

et al. 2022

Cancers

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“…The fact that pathological prion isoforms can remain dormant for an extended period of time may be another significant consideration in targeting dormancy in cancer. Cancer cells become dormant when they switch from an active to a quiescent state and cancer dormancy remains a major challenge in clinical oncology where tumor recurrence can resurface years after initial diagnosis [ 664 ]. Not surprisingly, stress has been identified as one of the triggers that can awaken cancer cells from dormancy [ 47 , 665 ], and hypoxic stress that reduces pH is able to activate prion aggregation [ 666 ] and phase separation ( Section 2.3.3 ).…”

Section: Melatonin May Promote Prp Physiological Functions and Inhibi...mentioning

confidence: 99%

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

Loh¹,

Reíter

2022

Molecules

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The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.

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“…Solitary disseminated primary tumor cells, once settled in the bone niche, may grow immediately or adopt a nonproliferating dormant state remaining quiescent in the bone marrow for up to decades (“cellular dormancy”) [ 78 , 86 , 87 ]. A comprehensive mechanistic insight into tumor dormancy, including its implications in tumor invasion and metastasis, has recently been provided [ 88 ]. For bone metastases, the fate of colonizing tumor cells most likely depends on their specific location in the bone microenvironment, where around 20% of the endosteal surface undergoes active remodeling, whereas the other 80% remains relatively quiescent at any given time [ 13 ].…”

Section: Mechanisms Of Metastasismentioning

confidence: 99%

Mechanisms, Diagnosis and Treatment of Bone Metastases

Ban

Fock

Aryee

et al. 2021

Cells

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Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients’ quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. We also highlight current and innovative approaches to biologically targeted therapy and immunotherapy. In particular, we discuss the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications. Multiple signaling pathways have been described to contribute to metastatic spread to the bone of specific cancer entities, with most knowledge derived from the study of breast and prostate cancer. However, it is likely that similar mechanisms are involved in different types of cancer, including multiple myeloma, primary bone sarcomas and neuroblastoma. The metastatic rate-limiting interaction of tumor cells with the various cellular and noncellular components of the bone-marrow niche provides attractive therapeutic targets, which are already partially exploited by novel promising immunotherapies.

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Tumor Dormancy: Implications for Invasion and Metastasis

Cited by 36 publications

References 123 publications

Role of Neural (N)-Cadherin in Breast Cancer Cell Stemness and Dormancy in the Bone Microenvironment

Role of Neural (N)-Cadherin in Breast Cancer Cell Stemness and Dormancy in the Bone Microenvironment

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

Mechanisms, Diagnosis and Treatment of Bone Metastases

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