Pathology, research and practice最新文献_第4页

Glutamine metabolites promote the progression of cervical cancer by inducing M2 macrophage polarization 谷氨酰胺代谢物通过诱导M2巨噬细胞极化促进宫颈癌的进展

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2025-12-29 DOI: 10.1016/j.prp.2025.156348

Tingting Liu , Lanyue Zhang , Yang Li, Wenxin Liao, Juexiao Deng, Hua Liang, Fujin Shen

Background

Tumour-associated macrophages (TAMs) within the tumour microenvironment play crucial roles in tumour initiation, invasion, and metastasis. While glutamine synthetase (GS) is expressed predominantly in the tumour stroma, particularly in TAMs, the role of glutamine metabolism in regulating TAM polarization and function in cervical cancer (CC) remains poorly understood. This study aims to clarify this role and its implications for cancer progression.

Methods

CD68 and GS expression in cervical tissues was detected using immunofluorescence staining. The effects of glutamine metabolism on TAM polarization were investigated via RTqPCR, flow cytometry, Western blotting and NAA treatment analyses. CCK8, colony formation, and Transwell assays were conducted to determine the effects of MSO-treated macrophages on tumour cell proliferation, migration, and invasion.

Results

We observed a significant increase in GS expression in TAMs within cervical cancer (CC) tissues, particularly in M2-like TAMs. Glutamine synthesized by TAMs with high GS expression was found to increase the proliferation, migration, and invasion of CC cells. Inhibition of GS in TAMs notably reduced their tumour-promoting effects. Additionally, the byproducts of glutamine metabolism in CC cells contributed to the polarization of TAMs towards the M2 phenotype. This polarization was completely abrogated when SNAT1, a key glutamine transporter, was inhibited in CC cells.

Conclusions

Our findings demonstrate that glutamine synthesized by TAMs with high GS expression promotes tumour progression in CC. Furthermore, glutamine byproducts produced by CC cells induce TAM polarization towards the M2 phenotype, suggesting crucial metabolic crosstalk between tumour cells and macrophages that supports tumour progression. These results highlight the potential of targeting glutamine metabolism to modulate TAM function and inhibit tumour growth.

肿瘤微环境中的肿瘤相关巨噬细胞（tam）在肿瘤的发生、侵袭和转移中起着至关重要的作用。虽然谷氨酰胺合成酶（GS）主要在肿瘤基质中表达，特别是在TAM中，但谷氨酰胺代谢在宫颈癌（CC）中调节TAM极化和功能的作用仍然知之甚少。本研究旨在阐明这一作用及其对癌症进展的影响。方法采用免疫荧光染色法检测宫颈组织中scd68和GS的表达。通过RTqPCR、流式细胞术、Western blotting和NAA处理分析，研究谷氨酰胺代谢对TAM极化的影响。通过CCK8、菌落形成和Transwell实验来确定mso处理巨噬细胞对肿瘤细胞增殖、迁移和侵袭的影响。结果我们观察到GS在宫颈癌（CC）组织中的表达显著增加，特别是在m2样tam中。高GS表达的tam合成谷氨酰胺可促进CC细胞的增殖、迁移和侵袭。在tam中抑制GS可显著降低其促肿瘤作用。此外，CC细胞中谷氨酰胺代谢的副产物有助于tam向M2表型极化。在CC细胞中，当关键的谷氨酰胺转运蛋白SNAT1被抑制时，这种极化被完全消除。结论研究结果表明，高GS表达的TAM合成谷氨酰胺可促进CC细胞的肿瘤进展，CC细胞产生的谷氨酰胺副产物可诱导TAM向M2表型极化，提示肿瘤细胞和巨噬细胞之间的关键代谢串扰支持肿瘤进展。这些结果强调了靶向谷氨酰胺代谢调节TAM功能和抑制肿瘤生长的潜力。

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引用次数: 0

Lactylation of HK2 facilitates cisplatin resistance in NSCLC by promoting cell migration, invasion, and glycolysis HK2的乳酸化通过促进细胞迁移、侵袭和糖酵解促进非小细胞肺癌的顺铂耐药

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2025-12-29 DOI: 10.1016/j.prp.2025.156349

Fanrui Zeng , Wenyang Wang , Peng Liu , Qingsi Zeng

Objective

Cisplatin (DDP) resistance has markedly diminished the efficacy of DDP-based chemotherapy in non-small cell lung cancer (NSCLC). Glycolysis represents a key contributor to NSCLC progression. Lactylation, a novel epigenetic modification, directly regulates glycolysis-associated gene expression. This study aimed to investigate whether lactylation-mediated modulation of glycolytic genes contributes to DDP resistance in NSCLC.

Methods

Cell viability, migration, and invasion capacities in parental and resistant NSCLC cells were assessed using cell counting kit-8 and Transwell migration/invasion assays. RT-qPCR and Western blot analyses were employed to quantify mRNA and protein levels of glycolytic markers. A xenografted tumor model was established to evaluate in vivo tumor progression.

Results

DDP-resistant NSCLC cells exhibited elevated glycolysis activity and increased lactylation levels of hexokinase 2 (HK2). Moreover, HK2 lysine lactylation (Kla) and protein stability were enhanced in resistant cells through suppression of ubiquitination. Functional experiments demonstrated that HK2 downregulation inhibited cell viability, migration, invasion, and glycolytic metabolism in A549/DDP and H1229/DDP cells, with these effects being reversed following sodium lactate treatment. Crucially, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) abrogated this rescue, and a K873R lactylation-deficient mutant failed to restore the malignant phenotype, confirming the specificity of the mechanism. In vivo studies further confirmed that HK2 inhibition suppressed tumor growth.

Conclusions

Lactylation at K873 stabilized HK2 by inhibiting its ubiquitination, which in turn drove glycolytic flux and promoted malignant behaviors in DDP-resistant NSCLC. This HK2 lactylation-stabilization axis represents a novel mechanism underlying chemoresistance and a promising therapeutic target for overcoming DDP resistance in NSCLC.

目的非小细胞肺癌（NSCLC）患者对铂（DDP）耐药显著降低了DDP化疗的疗效。糖酵解是NSCLC进展的关键因素。乳酸酰化是一种新的表观遗传修饰，直接调控糖酵解相关基因的表达。本研究旨在探讨乳酸化介导的糖酵解基因调节是否有助于NSCLC的DDP耐药。方法采用细胞计数试剂盒-8和Transwell迁移/侵袭试验评估亲代和耐药NSCLC细胞的细胞活力、迁移和侵袭能力。采用RT-qPCR和Western blot方法定量糖酵解标志物的mRNA和蛋白水平。建立异种移植肿瘤模型，评估肿瘤在体内的进展。结果耐药NSCLC细胞表现出糖酵解活性升高和己糖激酶2 （HK2）乳酸化水平升高。此外，通过抑制泛素化，抗性细胞中HK2赖氨酸乳酸化（Kla）和蛋白质稳定性增强。功能实验表明，HK2下调抑制了A549/DDP和H1229/DDP细胞的活力、迁移、侵袭和糖酵解代谢，乳酸钠处理后这些作用被逆转。至关重要的是，糖酵解抑制剂2-脱氧-d -葡萄糖（2-DG）消除了这种挽救作用，K873R乳酸化缺陷突变体未能恢复恶性表型，证实了其机制的特异性。体内研究进一步证实，抑制HK2抑制肿瘤生长。结论K873位点的乙酰化通过抑制其泛素化来稳定HK2，从而推动糖酵解通量，促进ddp耐药NSCLC的恶性行为。这个HK2乳酸化稳定轴代表了一种新的化疗耐药机制，也是克服非小细胞肺癌DDP耐药的一个有希望的治疗靶点。

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引用次数: 0

NEK8 stabilization via USP51-mediated deubiquitination promotes colorectal cancer progression 通过usp51介导的去泛素化来稳定NEK8促进结直肠癌的进展。

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2025-12-29 DOI: 10.1016/j.prp.2025.156346

Yizhang Wang , Min Lin , Meifang Zeng

NEK8 is a kinase involved in diverse cellular processes. Accumulating evidence has demonstrated that NEK8 contributes to the development of colorectal cancer (CRC). However, the regulation of its protein stability is poorly understood. Deubiquitinases, such as USP51, can keep protein levels stable by cleaving ubiquitin chains off. In this study, GEO analysis demonstrated elevated expression of USP51, while NEK8 mRNA levels showed no significant difference between CRC tissues and adjacent normal tissues, indicating post-transcriptional regulation. Immunohistochemistry showed a high expression of both NEK8 and USP51 proteins in cancer tissues and a positive correlation between them. Tissue microarray assay verified that NEK8 is an independent risk factor for CRC. In vitro functional experiments confirmed that NEK8 and USP51 promoted proliferation, colony formation, invasion, and migration of CRC, and a subcutaneous tumor formation assay further verified the oncogenic function of NEK8. Co-immunoprecipitation, co-immunofluorescence, ubiquitination assays, and functional rescue experiments proved that USP51 directly interacted with NEK8 and lowered the ubiquitination level of NEK8. Functional enrichment assays demonstrated that NEK8 modulates the WNT/β-catenin pathway. The knockdown of NEK8 resulted in decreased β-catenin protein levels. Taken together, our study reveals that the USP51-NEK8 axis promotes progression of CRC via the β-catenin pathway and could be a potential target for the treatment of CRC.

NEK8是一种参与多种细胞过程的激酶。越来越多的证据表明NEK8参与结直肠癌（CRC）的发展。然而，对其蛋白质稳定性的调控却知之甚少。去泛素酶，如USP51，可以通过切断泛素链来保持蛋白质水平的稳定。在本研究中，GEO分析显示USP51表达升高，而NEK8 mRNA水平在结直肠癌组织与邻近正常组织之间无显著差异，表明存在转录后调控。免疫组化显示NEK8和USP51蛋白在癌组织中均有高表达，且两者呈正相关。组织芯片检测证实NEK8是结直肠癌的独立危险因素。体外功能实验证实了NEK8和USP51促进CRC的增殖、集落形成、侵袭和迁移，皮下肿瘤形成实验进一步证实了NEK8的致癌功能。共免疫沉淀、共免疫荧光、泛素化实验和功能挽救实验证明USP51直接与NEK8相互作用，降低NEK8的泛素化水平。功能富集实验表明NEK8调节WNT/β-catenin通路。NEK8基因敲低导致β-连环蛋白水平降低。综上所述，我们的研究表明USP51-NEK8轴通过β-catenin途径促进CRC的进展，可能是治疗CRC的潜在靶点。

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引用次数: 0

Unveiling the role of PGCCs in tumor recurrence and therapeutic resistance: Hidden architects of cancer’s comeback 揭示PGCCs在肿瘤复发和治疗耐药中的作用：癌症复发的隐藏建筑师

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2025-12-29 DOI: 10.1016/j.prp.2025.156347

Mokhtar Rejili , Farid Hashemi

Polyploid Giant Cancer Cell (PGCCs) have emerged as pivotal players in cancer biology, contributing to tumor heterogeneity, recurrence, metastasis, and resistance to conventional therapies. Characterized by their enlarged size, aberrant nuclear morphology, and stem-like properties, PGCCs arise in response to environmental stressors such as chemotherapy, radiation, and hypoxia. These cells enter a dormant state, evade treatment, and later become reactivated to generate tumor-repopulating progeny through depolyploidization and asymmetric division (neosis). Daughter cells derived from PGCCs exhibit enhanced invasive capabilities, epithelial-to-mesenchymal transition (EMT), and metabolic adaptability, rendering PGCCs formidable obstacles in cancer management. Their unique biology involves complex molecular mechanisms including endoreplication, cell fusion, and autophagy, which facilitate survival and proliferation under stress conditions. Elucidating PGCC formation and behavior opens new avenues for targeted therapeutic strategies, encompassing immunomodulation, metabolic interference, and differentiation-based approaches. This paradigm shift in cancer research underscores the urgency for innovative diagnostic tools and personalized treatment modalities to effectively counter PGCC-driven malignancies.

多倍体巨癌细胞（Polyploid Giant Cancer Cell, PGCCs）在癌症生物学中扮演着关键角色，对肿瘤的异质性、复发、转移和对常规治疗的耐药性起着重要作用。pgcc的特点是体积增大、核形态异常和茎样性质，是对环境应激因素（如化疗、放疗和缺氧）的反应。这些细胞进入休眠状态，逃避治疗，然后重新激活，通过去多倍体和不对称分裂（新生）产生肿瘤再生的后代。pgcc衍生的子细胞表现出增强的侵袭能力、上皮-间质转化（EMT）和代谢适应性，使pgcc在癌症治疗中成为巨大的障碍。它们独特的生物学涉及复杂的分子机制，包括内复制、细胞融合和自噬，这些机制促进了应激条件下的生存和增殖。阐明PGCC的形成和行为为靶向治疗策略开辟了新的途径，包括免疫调节、代谢干扰和基于分化的方法。癌症研究的这种范式转变强调了创新诊断工具和个性化治疗方式的紧迫性，以有效对抗pgcc驱动的恶性肿瘤。

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引用次数: 0

RAB18 is upregulated in colorectal cancer and promotes tumor progression. RAB18在结直肠癌中表达上调，促进肿瘤进展。

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2025-12-25 DOI: 10.1016/j.prp.2025.156343

Hao Cheng , Suzeng Wang , Chunyu Yang , Feiyu Qin , Mengyuan Qian , Heyuan Jia , Kaiqing Wang , Surui Yao , Zhaohui Huang , Bojian Fei

RAB18 (Ras-related protein Rab-18) plays a crucial role in diverse cellular processes including autophagy, secretion and lipid droplet biogenesis. Recent studies suggest that RAB18 participates in tumorigenesis and progression. However, its role in colorectal cancer (CRC) is unclear. In this study, we observed significantly increased RAB18 expression in CRC tissues compared with paired normal tissues, which was associated with poor prognosis. RAB18 knockdown significantly inhibited cell proliferation, cell cycle progression, migration and invasion in CRC cells. Moreover, silencing RAB18 expression suppressed tumorigenesis in a mouse xenografted CRC model. Mechanistically, RNA-seq and pathway enrichment analyses suggested that RAB18 knockdown induced p53 pathway activation and decreased levels of E2F Targets and G2M checkpoint genes. Further validation identified stratifin (SFN) and mouse double minute 2 (MDM2) as potential downstream mediators of RAB18’s pro-tumorigenic effects in CRC. Collectively, our findings demonstrate the oncogenic role of RAB18 in CRC and highlight its potential as both a prognostic biomarker and a therapeutic target.

RAB18 （ras相关蛋白RAB18）在细胞自噬、分泌和脂滴生物形成等多种细胞过程中起着至关重要的作用。最近的研究表明RAB18参与了肿瘤的发生和发展。然而，其在结直肠癌（CRC）中的作用尚不清楚。在本研究中，我们观察到RAB18在结直肠癌组织中的表达与配对的正常组织相比显著升高，与预后不良相关。RAB18敲低可显著抑制结直肠癌细胞的增殖、细胞周期进展、迁移和侵袭。此外，在小鼠异种移植CRC模型中，沉默RAB18表达抑制肿瘤发生。在机制上，RNA-seq和途径富集分析表明，RAB18敲低诱导p53途径激活，降低E2F靶点和G2M检查点基因的水平。进一步验证发现，分层芬（SFN）和小鼠双分钟2 （MDM2）是RAB18在结直肠癌中促肿瘤作用的潜在下游介质。总的来说，我们的研究结果证明了RAB18在结直肠癌中的致癌作用，并强调了它作为预后生物标志物和治疗靶点的潜力。

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引用次数: 0

LDH-driven lactic acidosis in hypoxic solid tumors: Mechanisms of metastatic transformation and therapeutic opportunities 低氧实体瘤中ldh驱动的乳酸酸中毒：转移转化机制和治疗机会

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2025-12-25 DOI: 10.1016/j.prp.2025.156342

Priyanshu Kumar , Saumya Rastogi , Mandeep Kumar Arora , Lakhveer Singh

Lactic acidosis is a characteristic feature of solid hypoxic cancerous tumors, those that develop in the breast, colon, and prostate tissue. Even though extreme lactic acidosis is damaging to healthy cells, malignant tumors actually benefit from it in several different ways. Lactic acidosis in TME (TME) imparts resistance to chemotherapy and helps them from immune invasion. Lactic acidosis further benefits the tumor cells by inducing the formation of new blood vessels. Acidic tumour microenvironment (TME) provides very favourable pH conditions for activation of proteolytic enzymes like Matrix metalloproteinase (MMP-2/9), which helps the tumor cells invade into the nearby organs. Because aggressive hypoxic cancer cells have a high chance of metastasising to other organs, it is difficult to manage a tumor at this stage with chemotherapy. Stopping hypoxia-induced Lactate dehydrogenase (LDH) from working can prevent cancers from behaving aggressively. Restraining lactate circulation in the TME by inhibiting LDH and its transporters i.e Monocarboxylate transporters (MCT-1/2) would be a promising therapeutic strategy to prevent metastatic transformation of solid hypoxic tumors. Moreover, nanotechnology can be implicated in various ways to selectively kill the cancer cells. Whereas in some cancers, chemotherapeutic agents fail to activate, pH-sensitive nanoparticles can be designed to target such cancer cells. In the current review, we have highlighted the role and mechanisms of lactic acidosis to transform the benign tumours into more aggressive metastatic tumors. This review also offers fresh perspectives on the variety of LDH and MCT inhibitors currently undergoing clinical trials to act in the acidic TME.

乳酸性酸中毒是发生于乳腺、结肠和前列腺组织的实性缺氧癌性肿瘤的特征。尽管极度乳酸性酸中毒对健康细胞是有害的，但恶性肿瘤实际上以几种不同的方式从中受益。乳酸性酸中毒（TME）赋予TME对化疗的抵抗力，帮助其抵抗免疫入侵。乳酸酸中毒通过诱导新血管的形成进一步有利于肿瘤细胞。酸性肿瘤微环境（TME）为基质金属蛋白酶（MMP-2/9）等蛋白水解酶的激活提供了非常有利的pH条件，从而帮助肿瘤细胞侵入附近器官。由于侵袭性缺氧癌细胞有很高的机会转移到其他器官，因此很难用化疗来控制这个阶段的肿瘤。停止缺氧诱导的乳酸脱氢酶（LDH）的工作可以防止癌症的侵袭性行为。通过抑制LDH及其转运体，即单羧酸转运体（MCT-1/2）来抑制TME中的乳酸循环可能是一种很有前途的治疗策略，可以防止实体缺氧肿瘤的转移转化。此外，纳米技术可以通过多种方式选择性地杀死癌细胞。然而在某些癌症中，化疗药物无法激活，因此可以设计ph敏感纳米颗粒来靶向这些癌细胞。在当前的综述中，我们强调了乳酸酸中毒在将良性肿瘤转化为更具侵袭性的转移性肿瘤中的作用和机制。本综述还为目前正在进行临床试验的各种LDH和MCT抑制剂在酸性TME中的作用提供了新的视角。

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引用次数: 0

HOXC8 derived from cancer-associated fibroblasts regulates lung cancer cell malignant metastasis and ferroptosis by mediating the transcription of GCH1 源自癌症相关成纤维细胞的HOXC8通过介导GCH1的转录调控肺癌细胞恶性转移和铁凋亡

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2025-12-24 DOI: 10.1016/j.prp.2025.156345

Chao Qin , Xiaolei Shu , Wei Wang , Xin Wang , Yi Li , Xiaolong Li , Shu Lai , Yongpeng He

Background

In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a role in aggravating the tumor progression. However, research on its specific mechanisms of action remains insufficient. The aim of this study was to clarify the role of the transcription factor homeobox C8 (HOXC8) in CAFs and GTP cyclohydrolase I (GCH1) in the lung cancer.

Methods

MTT, EdU, Transwell, and stemness assays were employed to measure the biological behaviors of lung cancer cells. The ferroptosis-related indicators were determined by corresponding kits. The GEO database and TGCA samples were used to analyze the differentially expressed genes of CAFs after co-culture with lung cancer cells and the expression of HOXC8 in lung adenocarcinoma. Bioinformatics analysis and dual luciferase reporter system were used to detect the interaction between HOXC8 and GCH1. A xenograft tumor model and IHC staining were used to determine the effect of CAFs on tumor growth and GCH1 expression in vivo.

Results

CAFs accelerated lung cancer cell viability, proliferation, metastasis, sphere formation efficiency, and blocked ferroptosis-related indicators, but upregulated the HOXC8 level. The si-HOXC8-CAFs restrained the malignant progression of lung cancer cells. Interestingly, it was proved that HOXC8 bound to the promoter of GCH1 and induced its expression. Besides, overexpression of GCH1 rescued the effect of CAFs with knockdown of HOXC8 on lung cancer cells. CAFs with silenced HOXC8 inhibited tumor growth and GCH1 expression in vivo.

Conclusion

Our results indicate that CAFs-derived exosomes are a key source of HOXC8 in lung cancer cells. HOXC8 directly binds to the GCH1 promoter to activate its transcription, which in turn suppresses ferroptosis and promotes lung cancer progression. These findings contribute to the new intervention and treatment options for combating the malignant progression of lung cancer.

在肿瘤微环境（TME）中，癌症相关成纤维细胞（CAFs）在加速肿瘤进展中起着重要作用。然而，对其具体作用机制的研究仍然不足。本研究的目的是阐明转录因子同源盒C8 （HOXC8）在cas和GTP环水解酶I （GCH1）在肺癌中的作用。方法采用smtt法、EdU法、Transwell法和stemness法检测肺癌细胞的生物学行为。采用相应的试剂盒检测吸铁相关指标。利用GEO数据库和TGCA样本分析cas与肺癌细胞共培养后的差异表达基因及HOXC8在肺腺癌中的表达情况。采用生物信息学分析和双荧光素酶报告系统检测HOXC8与GCH1的相互作用。采用异种移植瘤模型和免疫组化染色法检测CAFs对肿瘤生长和体内GCH1表达的影响。结果scafs可促进肺癌细胞活力、增殖、转移、成球效率，抑制铁中毒相关指标，上调HOXC8水平。si-HOXC8-CAFs抑制肺癌细胞的恶性进展。有趣的是，HOXC8被证明与GCH1的启动子结合并诱导其表达。此外，过表达GCH1可通过抑制HOXC8来挽救cas对肺癌细胞的作用。在体内，HOXC8沉默的CAFs抑制肿瘤生长和GCH1的表达。结论cafs来源的外泌体是肺癌细胞HOXC8的重要来源。HOXC8直接结合GCH1启动子激活其转录，进而抑制铁下垂，促进肺癌进展。这些发现有助于对抗肺癌恶性进展的新的干预和治疗选择。

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引用次数: 0

Extracellular vesicles in tumor microenvironment modulation and clinical diagnosis 细胞外囊泡对肿瘤微环境的调节及临床诊断。

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2025-12-24 DOI: 10.1016/j.prp.2025.156339

Huan Liu , Dong Niu , Tong-Yao Yu , Yu-Hua Wang , Kun-Lin Ran , Yan-Hua Liu , Da-Chuan Yin , Chen-Yan Zhang

Extracellular vesicles (EVs) are key drivers of tumor metastasis and colonization. Their cargo, consisting of proteins, nucleic acids, and other biomolecules, functions as molecular messengers that trigger the epithelial-mesenchymal transition (EMT) process in tumor cells and facilitate immune evasion by releasing immunosuppressive factors to promote immune escape. Additionally, EVs influence intercellular interactions within the tumor microenvironment, facilitating angiogenesis, increasing vascular permeability, and supplying nutrients and oxygen to support tumor growth and metastasis. During metastasis, EVs protect circulating tumor cells (CTCs) from shear forces in the vascular network and attacks from the immune system. Furthermore, tumor-derived EVs facilitate the establishment of pre-metastatic niches (PMNs), thereby facilitating organ-specific metastasis. In this review, we overview the biogenesis and functions of EVs, as well as various factors that regulate their secretion. We systematically review tumor-derived EV functions in tumor progression, and also the effects of their interactions with other cells (such as adipocytes, immune cells, fibroblasts, and mesenchymal stem cells) in the tumor microenvironment was clarified. Additionally, we evaluate the diagnostic and prognostic potential of EVs as biomarkers for early tumor detection. The review also summarizes validated EV-associated biomarkers, offering a valuable foundation for the development of EV-based strategies in cancer diagnosis and therapy.

细胞外囊泡（EVs）是肿瘤转移和定植的关键驱动因素。它们的货物由蛋白质、核酸和其他生物分子组成，作为分子信使，在肿瘤细胞中触发上皮-间质转化（EMT）过程，并通过释放免疫抑制因子促进免疫逃逸，促进免疫逃逸。此外，ev影响肿瘤微环境中的细胞间相互作用，促进血管生成，增加血管通透性，并提供营养和氧气以支持肿瘤生长和转移。在转移过程中，ev保护循环肿瘤细胞（ctc）免受血管网络中的剪切力和免疫系统的攻击。此外，肿瘤来源的ev促进了转移前生态位（pmn）的建立，从而促进了器官特异性转移。本文就ev的生物发生、功能以及调控其分泌的各种因素作一综述。我们系统地回顾了肿瘤源性EV在肿瘤进展中的功能，并阐明了它们在肿瘤微环境中与其他细胞（如脂肪细胞、免疫细胞、成纤维细胞和间充质干细胞）相互作用的影响。此外，我们评估了ev作为早期肿瘤检测的生物标志物的诊断和预后潜力。本文还总结了验证的ev相关生物标志物，为开发基于ev的癌症诊断和治疗策略提供了有价值的基础。

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引用次数: 0

Mitochondrial-derived microproteins in cancer and neurodegeneration: A new era of cross-disease mechanistic insights 线粒体来源的微蛋白在癌症和神经变性：跨疾病机制的新时代见解。

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2025-12-23 DOI: 10.1016/j.prp.2025.156344

Shangtong Hu , Chunxiu Hu , Minfeng Tong

Mitochondrial-derived microproteins (MDPs) translate mitochondrial stress into cellular decisions that shape aging, metabolism, cancer biology, and neurodegeneration. Humanin, MOTS-c, SHLPs, and the recently identified SHMOOSE act through distinct intracellular and receptor-mediated pathways to regulate apoptosis, nutrient sensing, redox balance, and mito-nuclear communication. These programs confer neuroprotection in post-mitotic tissues but can be co-opted by tumors for survival, invasion, and therapy resistance, helping explain the inverse comorbidity between cancer and Alzheimer’s disease. This review synthesizes the divergent signaling architectures of major MDPs, including Humanin-FPR2/gp130, MOTS-c-AMPK/NRF2-LARS1/mTORC1, SHLP2-CXCR7, and SHMOOSE’s genotype-dependent activity, and outlines how these mechanisms produce disease-specific outcomes. Recent advances in mitoribosome profiling, DIA-based proteogenomics, and mitochondrial base editing have accelerated the discovery and functional characterization of MDPs. Emerging translational opportunities include MDP-targeted agonists, antagonists, and engineered delivery systems designed for application in neurodegenerative disorders and cancer. Overall, MDPs represent a druggable signaling layer whose context-dependent effects can be selectively directed across diseases.

线粒体衍生的微蛋白（MDPs）将线粒体应激转化为细胞决策，影响衰老、代谢、癌症生物学和神经变性。Humanin、MOTS-c、shlp和最近发现的SHMOOSE通过不同的细胞内和受体介导的途径调节细胞凋亡、营养感知、氧化还原平衡和mitto -nuclear通讯。这些程序赋予有丝分裂后组织的神经保护作用，但也可以被肿瘤吸收，用于生存、侵袭和治疗抵抗，这有助于解释癌症和阿尔茨海默病之间的逆共病。本文综述了主要MDPs的不同信号结构，包括Humanin-FPR2/gp130、MOTS-c-AMPK/NRF2-LARS1/mTORC1、SHLP2-CXCR7和SHMOOSE的基因型依赖性活性，并概述了这些机制如何产生疾病特异性结果。线粒体谱分析、基于dia的蛋白质基因组学和线粒体碱基编辑的最新进展加速了MDPs的发现和功能表征。新兴的转化机会包括针对mdp的激动剂、拮抗剂和设计用于神经退行性疾病和癌症的工程输送系统。总的来说，mdp代表了一个可药物化的信号层，其上下文依赖的作用可以选择性地针对疾病。

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引用次数: 0

The advancements in targeted therapeutic strategies for breast cancer via intervention of natural molecules: An insight into cellular and molecular mechanisms 通过自然分子干预的乳腺癌靶向治疗策略的进展：对细胞和分子机制的洞察。

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2025-12-23 DOI: 10.1016/j.prp.2025.156338

Mohammed Kaleem , Purushottam Gangane , Md Ali Mujtaba , Aachal Kanekar , Naiyer Shahzad , Abdullah R. Alzahrani , Ameeduzzafar Zafar , Aftab Ahmad

Breast cancer (BC) is the most common cancer and a major cause of cancer-related deaths in women worldwide. Its significant molecular heterogeneity leads to different response rates, leaving standard therapy approaches comparatively ineffective. Recent evidence highlights the promise of natural compound–based therapies in modulating oncogenic signaling, regulating epigenetic mechanisms, and reshaping the tumor microenvironment. This review systematically explores the anticancer potential of bioactive phytochemicals, including curcumin, resveratrol, thymoquinone, and berberine, in BC. These agents exhibit pleiotropic mechanisms such as promoting apoptosis (e.g., via p53 activation), suppressing angiogenesis (e.g., through VEGF downregulation), and reversing chemoresistance (e.g., by inhibiting the PI3K/AKT/mTOR axis). The role of epigenetic regulation is explored, focusing on DNA methylation, histone modifications, and non-coding RNAs. Compounds like EGCG and ellagic acid have been shown to restore the expression of tumor suppressor genes. Special attention is given to different types of breast cancer, especially triple-negative breast cancer (TNBC), which currently has limited treatment options and poor outcomes. Laboratory studies suggest that plant-based compounds can enhance the sensitivity of TNBC cells to standard chemotherapy, while also impacting immune and metabolic functions. Advances in nanotechnology, such as liposome-encapsulated curcumin, gold nanoparticles containing berberine, and nano-delivery systems for resveratrol, have improved the absorption and effectiveness of these substances. In conclusion, natural compounds represent a valuable source of novel therapeutics for breast cancer management, bridging molecular insights with translational potential.

乳腺癌（BC）是最常见的癌症，也是全世界妇女癌症相关死亡的主要原因。其显著的分子异质性导致不同的应答率，使标准治疗方法相对无效。最近的证据强调了以天然化合物为基础的疗法在调节致癌信号、调节表观遗传机制和重塑肿瘤微环境方面的前景。本文系统探讨了姜黄素、白藜芦醇、百里醌和小檗碱等生物活性植物化学物质在BC中的抗癌潜力。这些药物表现出多效性机制，如促进细胞凋亡（如通过p53激活）、抑制血管生成（如通过VEGF下调）和逆转化疗耐药（如通过抑制PI3K/AKT/mTOR轴）。探讨了表观遗传调控的作用，重点是DNA甲基化，组蛋白修饰和非编码rna。EGCG和鞣花酸等化合物已被证明可以恢复肿瘤抑制基因的表达。特别关注不同类型的乳腺癌，特别是三阴性乳腺癌（TNBC），目前治疗选择有限，结果不佳。实验室研究表明，基于植物的化合物可以增强TNBC细胞对标准化疗的敏感性，同时也会影响免疫和代谢功能。纳米技术的进步，如脂质体封装的姜黄素、含有小檗碱的金纳米颗粒和白藜芦醇的纳米递送系统，已经改善了这些物质的吸收和有效性。总之，天然化合物代表了乳腺癌治疗新疗法的宝贵来源，将分子见解与转化潜力联系起来。

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