Peritendinous adhesion formation (PAF) can substantially limit the range of motion of digits.However, the origin of myofibroblasts in PAF tissues is still unclear.In this study, we found that the concentration of active TGF-β1 and the numbers of macrophages, mesenchymal stromal cells (MSCs), and myofibroblasts in human and mouse adhesion tissues were increased.Furthermore, knockout of TGF-β1 in macrophages or TGF-β1R2 in MSCs inhibited PAF by reducing MSC and myofibroblast infiltration and collagen I and III deposition, resp.Moreover, we found that MSCs differentiated into myofibroblasts to form adhesion tissues.Systemic injection of the TGF-β-neutralizing antibody 1D11 during the granulation formation stage of PAF significantly reduced the infiltration of MSCs and myofibroblasts and, subsequently, PAF.These results suggest that macrophage-derived TGF-β1 recruits MSCs to form myofibroblasts in peritendinous adhesions.An improved understanding of PAF mechanisms could help identify a potential therapeutic strategy.

07 Apr 2023·Breast cancer research : BCR

PKC-ζ mediated reduction of the extracellular vesicles-associated TGF-β1 overcomes radiotherapy resistance in breast cancer.

Article

Author: Wang, Luoyang ; Liang, Wei ; Zhao, Ziran ; Zhang, Chunling ; Zhang, Fayun ; Wei, Wenjing ; Zeng, Wenfeng ; Zheng, Zifeng

BACKGROUNDRadiotherapy is widely applied in breast cancer treatment, while radiotherapy resistance is inevitable. TGF-β1 has been considered to be an endogenous factor for the development of radiotherapy resistance. As a large portion of TGF-β1 is secreted in an extracellular vesicles-associated form (TGF-β1_EV), particularly in radiated tumors. Thus, the understanding of the regulation mechanisms and the immunosuppressive functions of TGF-β1_EV will pave a way for overcoming the radiotherapy resistance in cancer treatment.METHODSThe superoxide-Zinc-PKC-ζ-TGF-β1_EV pathway in breast cancer cells was identified through sequence alignments of different PKC isoforms, speculation and experimental confirmation. A series of functional and molecular studies were performed by quantitative real-time PCR, western blot and flow cytometry analysis. Mice survival and tumor growth were recorded. Student's t test or two-way ANOVA with correction was used for comparisons of groups.RESULTSThe radiotherapy resulted in an increased expression of the intratumoral TGF-β1 and an enhanced infiltration of the Tregs in the breast cancer tissues. The intratumoral TGF-β1 was found mainly in the extracellular vesicles associated form both in the murine breast cancer model and in the human lung cancer tissues. Furthermore, radiation induced more TGF-β1_EV secretion and higher percentage of Tregs by promoting the expression and phosphorylation of protein kinase C zeta (PKC-ζ). Importantly, we found that naringenin rather than 1D11 significantly improved radiotherapy efficacy with less side effects. Distinct from TGF-β1 neutralizing antibody 1D11, the mechanism of naringenin was to downregulate the radiation-activated superoxide-Zinc-PKC-ζ-TGF-β1_EV pathway.CONCLUSIONSThe superoxide-zinc-PKC-ζ-TGF-β1_EV release pathway was elucidated to induce the accumulation of Tregs, resulting in radiotherapy resistance in the TME. Therefore, targeting PKC-ζ to counteract TGF-β1_EV function could represent a novel strategy to overcome radiotherapy resistance in the treatment of breast cancer or other cancers.TRIAL REGISTRATIONThe using of patient tissues with malignant Non-Small Cell Lung Cancer (NSCLC) was approved by the ethics committees at Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (NCC2022C-702, from June 8th, 2022).

01 Dec 2022·Journal of Bone Oncology

Preventing osteolytic lesions and osteomyelitis in multiple myeloma

Review

Author: Little, David G ; Dao, Aiken ; McDonald, Michelle M ; Schindeler, Aaron ; Savage, Paul B

Multiple myeloma is a hematological malignancy affecting the plasma cells. It is the second most common hematologic cancer in adults. Over 90% of patients develop local osteolytic lesions and skeletal-related events at some point during the progression of the disease. Bone lesions can induce severe pain and immobility and can also increase the risk of fractures and osteomyelitis. Skeletal complications are associated with poor clinical outcomes, affecting quality of life and mortality. Current standards of care for myeloma, e.g., autologous stem-cell transplantation (ASCT) and chemotherapy, do not lessen the risk of adverse events in bone. Once bone lesions are present, bone-targeted interventions are limited, with bone antiresorptive drugs being a mainstay of treatment. This review highlights the growing literature surrounding osteolytic lesions and bone infections associated with multiple myeloma and assesses current and emerging treatments. Emerging evidence from clinical trials suggests that denosumab can reduce skeletal-related events, and the potential application of bortezomib/1D11 can reduce bone destruction and pathological fractures in MM patients. Once established, bone lesions are prone to develop osteomyelitis - especially in immunocompromised individuals. Antibiotics and surgical interventions have been used to manage bone infections in most reported cases. As the bone infection risk associated with MM bone lesions become more evident, there is scope to improve patient management by mitigating this risk with prophylactic antimicrobial therapy.

100 Deals associated with 1D11 (Genzyme Corp.)

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Indication	Highest Phase	Country/Location	Organization	Date
Leukemia	Discovery	US	Genzyme Corp.	-
Metastatic Prostate Carcinoma	Discovery	US	Genzyme Corp.	-
Scleroderma, Systemic	Discovery	US	MedImmune Ltd.	-
Scleroderma, Systemic	Discovery	US	Genzyme Corp.	-

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