Therapy-Induced Senescence Drives Bone Loss

Yao, Zhangting; Murali, Bhavna; Ren, Qihao; Luo, Xianmin; Faget, Douglas V.; Cole, Tom; Ricci, Biancamaria; Thotala, Dinesh; Monahan, Joseph B.; Deursen, Jan M. van; Baker, Darren J.; Faccio, Roberta; Schwarz, Julie K.; Stewart, Sheila A.

doi:10.1158/0008-5472.can-19-2348

Cited by 88 publications

(94 citation statements)

References 56 publications

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“…In this context, Sheila Stewart discussed her findings related to the impact of senescence in chemotherapy-induced bone loss, a common comorbidity in cancer patients. Using a genetic mouse model, her team found that elimination of senescent cells that arise after chemotherapy prevented bone loss [58]. In addition, targeting SASP pathways using pharmacological inhibition of p38MAPK/MK2 signaling also limited chemotherapy-induced side effects [58].…”

Section: Prognostic and Therapeutic Implications Of Microenvironmentamentioning

confidence: 99%

“…Using a genetic mouse model, her team found that elimination of senescent cells that arise after chemotherapy prevented bone loss [58]. In addition, targeting SASP pathways using pharmacological inhibition of p38MAPK/MK2 signaling also limited chemotherapy-induced side effects [58]. Senescence is not only triggered by chemotherapy but occurs normally in healthy individuals, as part of the aging process, and may directly impact tumorigenesis.…”

Section: Prognostic and Therapeutic Implications Of Microenvironmentamentioning

confidence: 99%

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Deconstructing tumor heterogeneity: the stromal perspective

et al. 2020

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Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell Meeting Report Oncotarget 3622 www.oncotarget.com states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive versus suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field.

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Section: Prognostic and Therapeutic Implications Of Microenvironmentamentioning

confidence: 99%

Section: Prognostic and Therapeutic Implications Of Microenvironmentamentioning

confidence: 99%

Deconstructing tumor heterogeneity: the stromal perspective

et al. 2020

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“…However, studies based on therapy-induced senescence (TIS) indicated the emergence of adverse effects on cancer treatment (95,96). Chemotherapy-induced SASP drives bone loss in breast cancer and its regulation by p38-MAPK-MK2 inhibition could preserve bone, improving the quality of life of patients (97). TIS may contribute to unwanted outcomes through the stimulation of inflammation by increased secretion of SASP factors, the induction of senescence-associated stemness phenotype or senescence cell scape and further proliferation recovery (98-100).…”

Section: The Dual Interface Of Autophagy and Senescencementioning

confidence: 99%

Emerging Autophagy Functions Shape the Tumor Microenvironment and Play a Role in Cancer Progression - Implications for Cancer Therapy

et al. 2020

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The tumor microenvironment (TME) is a complex environment where cancer cells reside and interact with different types of cells, secreted factors, and the extracellular matrix. Additionally, TME is shaped by several processes, such as autophagy. Autophagy has emerged as a conserved intracellular degradation pathway for clearance of damaged organelles or aberrant proteins. With its central role, autophagy maintains the cellular homeostasis and orchestrates stress responses, playing opposite roles in tumorigenesis. During tumor development, autophagy also mediates autophagy-independent functions associated with several hallmarks of cancer, and therefore exerting several effects on tumor suppression and/or tumor promotion mechanisms. Beyond the concept of degradation, new different forms of autophagy have been described as modulators of cancer progression, such as secretory autophagy enabling intercellular communication in the TME by cargo release. In this context, the synthesis of senescence-associated secretory proteins by autophagy lead to a senescent phenotype. Besides disturbing tumor treatment responses, autophagy also participates in innate and adaptive immune signaling. Furthermore, recent studies have indicated intricate crosstalk between autophagy and the epithelial-mesenchymal transition (EMT), by which cancer cells obtain an invasive phenotype and metastatic potential. Thus, autophagy in the cancer context is far broader and complex than just a cell energy sensing mechanism. In this scenario, we will discuss the key roles of autophagy in the TME and surrounding cells, contributing to cancer development and progression/EMT. Finally, the potential intervention in autophagy processes as a strategy for cancer therapy will be addressed.

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“…For example, limiting therapy-induced SASPs by inhibiting the p38 MAPK-MK2 pathway could rescue chemotherapy-induced bone loss in doxorubicin-treated mouse models. 17 Wang et al found that TIS cells became vulnerable to apoptosis induction by ABT263 in vitro, and demonstrated the feasibility of the sequential therapy for cancer in which senotherapy could be administered concomitantly or after senescence-inducing treatment. 25 In preclinical mouse models of ovarian and breast cancer, concurrent PARPi and ABT263 treatment was observed to have a significant potentiation of cell killing.…”

Section: Targeting Senescence Cancer Cellsmentioning

confidence: 99%

The Dynamic Process and Its Dual Effects on Tumors of Therapy-Induced Senescence

Liao¹,

Xiao²,

Liu³

2020

CMAR

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Cellular senescence is traditionally considered as stable cell cycle arrest state with other phenotypic alterations including the production of an array of cytokines and growth factors. Cancer cells undergo senescence in response to chemotherapeutic agents, radiotherapy and molecular targeted therapy. This form of senescence is termed therapy-induced senescence (TIS) and represents a desirable target in cancer therapy. Recent studies have shown that cellular senescence is a highly heterogeneous and dynamic process. Apart from being cleared by the immune system, the senescent cancer cells may survive for a long time and escape from senescence state. Notably, these cells even have the potential to regain stemlike state with high aggressiveness that eventually facilitates cancer recurrence. Furthermore, the senescence-associated secretory phenotype (SASP) of senescent cells is not always the same, and could establish immunosuppression and a protumor microenvironment. Given these detrimental effects, senescence-inducing chemotherapy followed by senotherapy (the "one-two punch" approach), has emerged. This combined therapy could mitigate unnecessary side effects of the persistent senescent cells, reduce the toxicity of pro-senescence therapy and prolong the survival of cancer patients, and it has a potential future in the precise treatment of cancer. Herein, we review the complex effects of therapy-induced senescence in cancer and highlight the great promise of two-step strategies in anticancer therapies.

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Therapy-Induced Senescence Drives Bone Loss

Cited by 88 publications

References 56 publications

Deconstructing tumor heterogeneity: the stromal perspective

Deconstructing tumor heterogeneity: the stromal perspective

Emerging Autophagy Functions Shape the Tumor Microenvironment and Play a Role in Cancer Progression - Implications for Cancer Therapy

The Dynamic Process and Its Dual Effects on Tumors of Therapy-Induced Senescence

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