Comparative impact of proton versus photon irradiation on triple-negative breast cancer: Role of VEGFC in tumour aggressiveness

IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Saharnaz Sarlak, Delphine Marotte, Arthur Karaulic, Jessy Sirera, Alessandra Pierantoni, Meng-Chen Tsai, Roxane Sylvestre, Clement Molina, Arthur Gouraud, Aurélien Bancaud, Paraskevi Kousteridou, Marie Vidal, Joël Hérault, Jérôme Doyen, Maeva Dufies, Florent Morfoisse, Barbara Garmy-Susini, Frédéric Luciano, Gilles Pagès
{"title":"Comparative impact of proton versus photon irradiation on triple-negative breast cancer: Role of VEGFC in tumour aggressiveness","authors":"Saharnaz Sarlak,&nbsp;Delphine Marotte,&nbsp;Arthur Karaulic,&nbsp;Jessy Sirera,&nbsp;Alessandra Pierantoni,&nbsp;Meng-Chen Tsai,&nbsp;Roxane Sylvestre,&nbsp;Clement Molina,&nbsp;Arthur Gouraud,&nbsp;Aurélien Bancaud,&nbsp;Paraskevi Kousteridou,&nbsp;Marie Vidal,&nbsp;Joël Hérault,&nbsp;Jérôme Doyen,&nbsp;Maeva Dufies,&nbsp;Florent Morfoisse,&nbsp;Barbara Garmy-Susini,&nbsp;Frédéric Luciano,&nbsp;Gilles Pagès","doi":"10.1002/ctm2.70330","DOIUrl":null,"url":null,"abstract":"<p>Dear Editor,</p><p>In this study, we demonstrated that proton (P) and photon (X) radiotherapies (RT) lead to different molecular changes in triple-negative breast cancer (TNBC) cells. P-irradiated tumours tended to make larger tumours, while X-irradiated ones exhibited increased aggressiveness. Both types of radiation increased gene expression related to angiogenesis (blood vessel formation) and lymphangiogenesis (lymph vessel formation), which are associated with more aggressive cancer behaviour. We also found that targeting the lymphangiogenesis-related gene, vascular endothelial growth factor C (VEGFC), alongside either type of RT, could improve the prognosis for TNBC patients.</p><p>Breast cancer (BC) is the most common type of cancer among women.<span><sup>1</sup></span> Its aggressive forms, like TNBC, tend to be highly vascularized and often have an increased network of lymphatic vessels, which allows the cancer to metastasize more rapidly.<span><sup>2</sup></span> Standard treatment involves with a combination of surgery, chemotherapy and RT to target both local and systemic diseases. Despite these treatments, recurrence remains a significant challenge in aggressive forms of BC.<span><sup>3</sup></span></p><p>Proton therapy, a newer form of RT, offers more precise targeting than conventional X-RT, potentially reducing side effects by narrowing the radiation field.<span><sup>4</sup></span> Ongoing clinical trials are investigating whether P-RT might offer advantages over conventional X-RT, as recent research suggests promising advantages.<span><sup>5</sup></span></p><p>Here, we investigated how irradiation impacts TNBC cell behaviour and their microenvironment, building on our prior study of P- and X-RT effects on head and neck cancer.<span><sup>6</sup></span> Specifically, we investigated whether irradiation might inadvertently promote tumour growth by altering cells to release growth factors or cytokines that support tumour survival and progression.</p><p>To examine these effects, we developed TNBC cell populations (MDAMB231 and BT549) that are resilient to repeated X- or P-RT. The traits of aggressiveness, such as proliferation and migration were evaluated in these multi-irradiated cells. While proliferation rates in irradiated cells were like controls (Figure 1A,B), migration abilities were enhanced (Figure 1C,D), suggesting that these cells could have a greater potential for metastasis. This increase in migration mirrors findings in X-resistant medulloblastoma cells.<span><sup>7</sup></span></p><p>Since metastasis in TNBC frequently occurs via lymphatic vessels,<span><sup>8</sup></span> we investigated the impact of X- and P-RT on the expression of VEGFC, a key regulator of lymphangiogenesis, in our TNBC cell lines which exhibit higher basal levels of VEGFC compared to cell lines of other BC subtypes (Figure S1). Both irradiation types significantly upregulated VEGFC mRNA expression (Figure 1E) and increased secretion of VEGFC protein (Figure 1F), (similar trend in BT549 cells). A comparable increase in VEGFC mRNA levels was also noted when comparing single versus multiple rounds of RT (Figure S2). Higher VEGFC expression has been associated with worse clinical outcomes in TNBC, as evidenced by patient survival data from existing databases (KM plotter software) (Figure 1G), suggesting that both baseline VEGFC levels and RT-induced VEGFC upregulation could contribute to worse prognosis in TNBC. This elevated VEGFC expression indicates a potential risk of enhanced lymphangiogenesis, and thus higher recurrence and metastasis.<span><sup>9</sup></span></p><p>Other genes linked to poor survival, such as artemin, angiopoietin 2, IGFBP2, FAP and TGFβ were also differentially expressed after irradiation in both cell lines, further suggesting that radiation may subtly alter gene expression in ways that could increase relapse risk (Figure 1H). Individual data for each factor are presented in Figure S3. These findings emphasize the need to consider the distinct impacts of different radiation types on the tumour cells and the surrounding microenvironment when devising TNBC treatment strategies.</p><p>Furthermore, the aggressiveness and the capacity of the multi-irradiated cells to promote metastasis via lymphatic vessels was evaluated by permeability assay. Vessel-on-chip experiments using reconstituted lymphatic vessels surrounded by multi-irradiated X-irradiated MDAMB231 cells demonstrated increased vessel leakiness compared to vessels exposed to either control or multi-irradiated P-irradiated MDAMB231 cells (Figure 2A,B), suggesting enhanced metastatic potential. Considering the aggressive behaviour observed in vitro in TNBC cells adapted to repeated irradiations, we conducted experiments to assess the tumourigenic capacity of TNBC P- and X-adapted cells in nude mice. Tumours from P-adapted cells had higher incidence (100%) compared to 60% in X-adapted, and 40% in controls (Figure 2C) and were larger than those from X-adapted or control cells (Figure 2D,E). However, X-irradiated tumours, though smaller, showed higher expression of lymphatic (Lyve1) and vascular markers (CD31), indicating a more aggressive molecular profile than P-irradiated tumours (Figure 2F–I). Moreover, VEGFC protein expression was elevated in X-irradiated tumour lysates compared to both P-irradiated and control (C) tumours (Figure 2J). Transcriptomic analysis performed on human genes (tumours cells) and mouse genes (microenvironment) revealed that X tumours had more active pathways for angiogenesis, lymphangiogenesis and other genes associated with aggressiveness such as those involved in epithelial-mesenchymal transition (Figure S4A,B). This suggests that X-irradiated tumours may carry a higher risk of aggressive relapse.</p><p>Proteomic analysis of the tumour tissues revealed distinct molecular profiles between the two irradiation types (Figure S5A). The unique protein signatures in P- and X-irradiated tumours were confirmed using Principal Component Analysis (PCA), which showed clear separation between the two types based on their protein expression (Figure S5B). This result underscores that P- and X-RT impact TNBC tumour biology in different ways.</p><p>To investigate the role of VEGFC in radiation response, we used CRIPRS/Cas9 to knockout the VEGFC gene in MDAMB231 and BT549 cell lines (Table S1, Figure S6). VEGFC-deficient cells (VEGFC-/-) had significantly lower survival rates after X- or P-RT compared to controls, with almost no viable VEGFC-/- cells remaining (Figure 3A–D). However, VEGFC knockout did not affect the cells' response to chemotherapy, indicating VEGFC's specific influence on RT sensitivity (Figure S7A–C). Furthermore, VEGFC knockout did not affect cell proliferation in vitro (Figure 3E,F). To assess the role of VEGFC in modulating sensitivity to RT, MDAMB231 cells were exposed to high-dose RT (8 Gy) with or without preincubation with recombinant VEGFC protein. While both X- and P-RT significantly reduced cell numbers, preincubation with VEGFC conferred a protective effect (Figure S8). This finding is consistent with our previous observation that VEGFC-/- cells exhibit heightened sensitivity to RT.</p><p>In a related in vitro experiment, treatment with an anti-VEGFC antibody reduced cell counts by up to 90% in both control and multi-irradiated X- and P-irradiated cells, suggesting that endogenous and RT-induced VEGFC function as an autocrine factor promoting proliferation and/or survival (Figure 4A,B). Anti-VEGFC antibody treatment inhibited the growth of experimental tumours in nude mice derived from control as well as multi-irradiated X- and P-irradiated MDAMB231 cells, with some tumours exhibiting near-complete regression (Figure 4C–E). This suggests that anti-VEGFC therapy, especially alongside RT, could be an effective strategy to limit TNBC progression.</p><p>In conclusion, our study reveals that P and X radiotherapies produce different molecular effects in TNBC cells, with P-irradiated tumours being larger and X-irradiated tumours displaying more aggressive molecular characteristics. These differences suggest that X-RT may lead to more aggressive relapses if resistant cells survive. Future research should focus on understanding these radiation-specific effects and developing strategies to manage risks associated with X-RT. Furthermore, our study emphasizes the potential of anti-VEGFC therapies, especially if administered before irradiation, to counteract radiation-induced molecular changes. Comparative clinical trials and further investigations into anti-VEGFC treatment schedules are anticipated to advance TNBC treatment strategies.</p><p><i>Conception and design</i>: Gilles Pagès and Frédéric Luciano. <i>Development of methodology</i>: Saharnaz Sarlak. <i>Acquisition of data</i>: Saharnaz Sarlak, Delphine Marotte, Alessandra Pierantoni, Jessy Sirera, Meng-Chen Tsai, Arthur Karaulic and Roxane Sylvestre. <i>Analysis and interpretation of data</i>: Saharnaz Sarlak, Florent Morfoisse, Barbara Garmy-Susini, Frédéric Luciano, Gilles Pagès and Paraskevi Kousteridou. <i>Writing, review</i>: Saharnaz Sarlak, Florent Morfoisse, Meng-Chen Tsai, Frédéric Luciano and Gilles Pagès. <i>Administrative, technical, or material support</i>: Marie Vidal, Joël Hérault and Gilles Pagès. <i>Study supervision</i>: Frédéric Luciano and Gilles Pagès.</p><p>The authors declare no conflicts of interest.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9000,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70330","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70330","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

Abstract

Dear Editor,

In this study, we demonstrated that proton (P) and photon (X) radiotherapies (RT) lead to different molecular changes in triple-negative breast cancer (TNBC) cells. P-irradiated tumours tended to make larger tumours, while X-irradiated ones exhibited increased aggressiveness. Both types of radiation increased gene expression related to angiogenesis (blood vessel formation) and lymphangiogenesis (lymph vessel formation), which are associated with more aggressive cancer behaviour. We also found that targeting the lymphangiogenesis-related gene, vascular endothelial growth factor C (VEGFC), alongside either type of RT, could improve the prognosis for TNBC patients.

Breast cancer (BC) is the most common type of cancer among women.1 Its aggressive forms, like TNBC, tend to be highly vascularized and often have an increased network of lymphatic vessels, which allows the cancer to metastasize more rapidly.2 Standard treatment involves with a combination of surgery, chemotherapy and RT to target both local and systemic diseases. Despite these treatments, recurrence remains a significant challenge in aggressive forms of BC.3

Proton therapy, a newer form of RT, offers more precise targeting than conventional X-RT, potentially reducing side effects by narrowing the radiation field.4 Ongoing clinical trials are investigating whether P-RT might offer advantages over conventional X-RT, as recent research suggests promising advantages.5

Here, we investigated how irradiation impacts TNBC cell behaviour and their microenvironment, building on our prior study of P- and X-RT effects on head and neck cancer.6 Specifically, we investigated whether irradiation might inadvertently promote tumour growth by altering cells to release growth factors or cytokines that support tumour survival and progression.

To examine these effects, we developed TNBC cell populations (MDAMB231 and BT549) that are resilient to repeated X- or P-RT. The traits of aggressiveness, such as proliferation and migration were evaluated in these multi-irradiated cells. While proliferation rates in irradiated cells were like controls (Figure 1A,B), migration abilities were enhanced (Figure 1C,D), suggesting that these cells could have a greater potential for metastasis. This increase in migration mirrors findings in X-resistant medulloblastoma cells.7

Since metastasis in TNBC frequently occurs via lymphatic vessels,8 we investigated the impact of X- and P-RT on the expression of VEGFC, a key regulator of lymphangiogenesis, in our TNBC cell lines which exhibit higher basal levels of VEGFC compared to cell lines of other BC subtypes (Figure S1). Both irradiation types significantly upregulated VEGFC mRNA expression (Figure 1E) and increased secretion of VEGFC protein (Figure 1F), (similar trend in BT549 cells). A comparable increase in VEGFC mRNA levels was also noted when comparing single versus multiple rounds of RT (Figure S2). Higher VEGFC expression has been associated with worse clinical outcomes in TNBC, as evidenced by patient survival data from existing databases (KM plotter software) (Figure 1G), suggesting that both baseline VEGFC levels and RT-induced VEGFC upregulation could contribute to worse prognosis in TNBC. This elevated VEGFC expression indicates a potential risk of enhanced lymphangiogenesis, and thus higher recurrence and metastasis.9

Other genes linked to poor survival, such as artemin, angiopoietin 2, IGFBP2, FAP and TGFβ were also differentially expressed after irradiation in both cell lines, further suggesting that radiation may subtly alter gene expression in ways that could increase relapse risk (Figure 1H). Individual data for each factor are presented in Figure S3. These findings emphasize the need to consider the distinct impacts of different radiation types on the tumour cells and the surrounding microenvironment when devising TNBC treatment strategies.

Furthermore, the aggressiveness and the capacity of the multi-irradiated cells to promote metastasis via lymphatic vessels was evaluated by permeability assay. Vessel-on-chip experiments using reconstituted lymphatic vessels surrounded by multi-irradiated X-irradiated MDAMB231 cells demonstrated increased vessel leakiness compared to vessels exposed to either control or multi-irradiated P-irradiated MDAMB231 cells (Figure 2A,B), suggesting enhanced metastatic potential. Considering the aggressive behaviour observed in vitro in TNBC cells adapted to repeated irradiations, we conducted experiments to assess the tumourigenic capacity of TNBC P- and X-adapted cells in nude mice. Tumours from P-adapted cells had higher incidence (100%) compared to 60% in X-adapted, and 40% in controls (Figure 2C) and were larger than those from X-adapted or control cells (Figure 2D,E). However, X-irradiated tumours, though smaller, showed higher expression of lymphatic (Lyve1) and vascular markers (CD31), indicating a more aggressive molecular profile than P-irradiated tumours (Figure 2F–I). Moreover, VEGFC protein expression was elevated in X-irradiated tumour lysates compared to both P-irradiated and control (C) tumours (Figure 2J). Transcriptomic analysis performed on human genes (tumours cells) and mouse genes (microenvironment) revealed that X tumours had more active pathways for angiogenesis, lymphangiogenesis and other genes associated with aggressiveness such as those involved in epithelial-mesenchymal transition (Figure S4A,B). This suggests that X-irradiated tumours may carry a higher risk of aggressive relapse.

Proteomic analysis of the tumour tissues revealed distinct molecular profiles between the two irradiation types (Figure S5A). The unique protein signatures in P- and X-irradiated tumours were confirmed using Principal Component Analysis (PCA), which showed clear separation between the two types based on their protein expression (Figure S5B). This result underscores that P- and X-RT impact TNBC tumour biology in different ways.

To investigate the role of VEGFC in radiation response, we used CRIPRS/Cas9 to knockout the VEGFC gene in MDAMB231 and BT549 cell lines (Table S1, Figure S6). VEGFC-deficient cells (VEGFC-/-) had significantly lower survival rates after X- or P-RT compared to controls, with almost no viable VEGFC-/- cells remaining (Figure 3A–D). However, VEGFC knockout did not affect the cells' response to chemotherapy, indicating VEGFC's specific influence on RT sensitivity (Figure S7A–C). Furthermore, VEGFC knockout did not affect cell proliferation in vitro (Figure 3E,F). To assess the role of VEGFC in modulating sensitivity to RT, MDAMB231 cells were exposed to high-dose RT (8 Gy) with or without preincubation with recombinant VEGFC protein. While both X- and P-RT significantly reduced cell numbers, preincubation with VEGFC conferred a protective effect (Figure S8). This finding is consistent with our previous observation that VEGFC-/- cells exhibit heightened sensitivity to RT.

In a related in vitro experiment, treatment with an anti-VEGFC antibody reduced cell counts by up to 90% in both control and multi-irradiated X- and P-irradiated cells, suggesting that endogenous and RT-induced VEGFC function as an autocrine factor promoting proliferation and/or survival (Figure 4A,B). Anti-VEGFC antibody treatment inhibited the growth of experimental tumours in nude mice derived from control as well as multi-irradiated X- and P-irradiated MDAMB231 cells, with some tumours exhibiting near-complete regression (Figure 4C–E). This suggests that anti-VEGFC therapy, especially alongside RT, could be an effective strategy to limit TNBC progression.

In conclusion, our study reveals that P and X radiotherapies produce different molecular effects in TNBC cells, with P-irradiated tumours being larger and X-irradiated tumours displaying more aggressive molecular characteristics. These differences suggest that X-RT may lead to more aggressive relapses if resistant cells survive. Future research should focus on understanding these radiation-specific effects and developing strategies to manage risks associated with X-RT. Furthermore, our study emphasizes the potential of anti-VEGFC therapies, especially if administered before irradiation, to counteract radiation-induced molecular changes. Comparative clinical trials and further investigations into anti-VEGFC treatment schedules are anticipated to advance TNBC treatment strategies.

Conception and design: Gilles Pagès and Frédéric Luciano. Development of methodology: Saharnaz Sarlak. Acquisition of data: Saharnaz Sarlak, Delphine Marotte, Alessandra Pierantoni, Jessy Sirera, Meng-Chen Tsai, Arthur Karaulic and Roxane Sylvestre. Analysis and interpretation of data: Saharnaz Sarlak, Florent Morfoisse, Barbara Garmy-Susini, Frédéric Luciano, Gilles Pagès and Paraskevi Kousteridou. Writing, review: Saharnaz Sarlak, Florent Morfoisse, Meng-Chen Tsai, Frédéric Luciano and Gilles Pagès. Administrative, technical, or material support: Marie Vidal, Joël Hérault and Gilles Pagès. Study supervision: Frédéric Luciano and Gilles Pagès.

The authors declare no conflicts of interest.

质子与光子照射对三阴性乳腺癌的比较影响:VEGFC在肿瘤侵袭性中的作用
在这项研究中,我们证明了质子(P)和光子(X)放疗(RT)导致三阴性乳腺癌(TNBC)细胞的不同分子变化。p照射的肿瘤倾向于形成更大的肿瘤,而x照射的肿瘤表现出更强的侵袭性。两种类型的辐射都增加了与血管生成(血管形成)和淋巴管生成(淋巴管形成)相关的基因表达,这与更具侵袭性的癌症行为有关。我们还发现,靶向淋巴管生成相关基因血管内皮生长因子C (VEGFC),以及任何一种类型的RT,都可以改善TNBC患者的预后。乳腺癌(BC)是女性中最常见的癌症其侵袭性形式,如TNBC,往往是高度血管化的,通常有增加的淋巴管网络,这使得癌症转移更快标准治疗包括手术、化疗和放疗相结合,针对局部和全身性疾病。3 .质子治疗是一种较新的放射治疗形式,比传统的X-RT提供更精确的靶向,通过缩小放射范围潜在地减少副作用正在进行的临床试验正在调查P-RT是否比传统的X-RT有优势,因为最近的研究表明有希望的优势。在此,我们基于先前对P-和X-RT对头颈癌的影响的研究,研究了辐射如何影响TNBC细胞的行为及其微环境具体来说,我们研究了辐照是否可能通过改变细胞释放支持肿瘤生存和进展的生长因子或细胞因子而无意中促进肿瘤生长。为了检验这些影响,我们开发了TNBC细胞群(MDAMB231和BT549),它们对重复的X-或P-RT具有弹性。对这些细胞的侵袭性,如增殖和迁移进行了评价。虽然辐照细胞的增殖率与对照组相似(图1A,B),但迁移能力增强(图1C,D),表明这些细胞可能具有更大的转移潜力。这种迁移的增加反映了x耐药髓母细胞瘤细胞的发现。由于TNBC的转移经常通过淋巴管发生,我们研究了X-和P-RT对VEGFC表达的影响,VEGFC是淋巴管生成的关键调节因子,在我们的TNBC细胞系中,与其他BC亚型细胞系相比,VEGFC的基础水平更高(图S1)。两种辐照方式均显著上调了VEGFC mRNA的表达(图1E),并增加了VEGFC蛋白的分泌(图1F)(在BT549细胞中趋势相似)。当比较单轮和多轮RT时,也注意到VEGFC mRNA水平的相应增加(图S2)。现有数据库(KM绘图仪软件)的患者生存数据证明,高VEGFC表达与TNBC中较差的临床结果相关(图1G),这表明基线VEGFC水平和rt诱导的VEGFC上调都可能导致TNBC中较差的预后。VEGFC表达的升高表明淋巴管生成增强的潜在风险,因此更高的复发和转移。其他与生存不良相关的基因,如阿耳特明、血管生成素2、IGFBP2、FAP和TGFβ,在两种细胞系中辐照后也有差异表达,进一步表明辐射可能以微妙的方式改变基因表达,从而增加复发风险(图1H)。图S3给出了每个因素的单独数据。这些发现强调,在设计TNBC治疗策略时,需要考虑不同类型的辐射对肿瘤细胞和周围微环境的不同影响。此外,通过渗透性试验评估了多次照射细胞的侵袭性和促进淋巴管转移的能力。用x射线照射MDAMB231细胞包围重建淋巴管的血管芯片实验显示,与暴露于对照或多次p射线照射MDAMB231细胞的血管相比,血管渗漏增加(图2A,B),表明转移潜力增强。考虑到TNBC细胞在体外适应多次辐照后的侵袭行为,我们在裸鼠身上进行了实验,以评估TNBC P和x适应细胞的致瘤能力。来自p适应细胞的肿瘤发生率(100%)高于x适应细胞的60%和对照组的40%(图2C),并且大于来自x适应细胞或对照细胞的肿瘤(图2D,E)。然而,x照射肿瘤虽然较小,但淋巴(Lyve1)和血管标志物(CD31)的表达更高,表明其分子谱比p照射肿瘤更具侵袭性(图2f - 1)。 此外,与p照射和对照(C)肿瘤相比,x照射肿瘤裂解物中VEGFC蛋白表达升高(图2J)。对人类基因(肿瘤细胞)和小鼠基因(微环境)进行的转录组学分析显示,X肿瘤具有更活跃的血管生成、淋巴管生成和其他与侵袭性相关的基因(如参与上皮-间质转化的基因)的途径(图S4A,B)。这表明x射线照射的肿瘤可能具有更高的侵袭性复发风险。肿瘤组织的蛋白质组学分析显示两种照射类型之间存在不同的分子谱(图S5A)。使用主成分分析(PCA)证实了P和x照射肿瘤中独特的蛋白质特征,根据它们的蛋白质表达,两种类型之间存在明显的分离(图S5B)。这一结果强调了P-和X-RT以不同的方式影响TNBC肿瘤生物学。为了研究VEGFC在辐射应答中的作用,我们使用crisprs /Cas9敲除MDAMB231和BT549细胞系中的VEGFC基因(表S1,图S6)。与对照组相比,X-或P-RT后VEGFC缺陷细胞(VEGFC-/-)的存活率显著降低,几乎没有存活的VEGFC-/-细胞(图3A-D)。然而,VEGFC敲除不影响细胞对化疗的反应,表明VEGFC对RT敏感性有特异性影响(图S7A-C)。此外,敲除VEGFC不影响细胞体外增殖(图3E,F)。为了评估VEGFC在调节RT敏感性中的作用,将MDAMB231细胞暴露于高剂量RT (8 Gy)中,并与重组VEGFC蛋白进行预孵育。虽然X-和P-RT都能显著减少细胞数量,但与VEGFC预孵育具有保护作用(图S8)。这一发现与我们之前的观察结果一致,即VEGFC-/-细胞对rt表现出更高的敏感性。在一项相关的体外实验中,在对照和多次辐照的X-和p -辐照细胞中,抗VEGFC抗体可使细胞计数减少高达90%,这表明内源性和rt诱导的VEGFC是一种促进增殖和/或存活的自分泌因子(图4A,B)。抗vegfc抗体治疗抑制了裸鼠实验肿瘤的生长,裸鼠来源于对照以及多次辐照的X和p辐照的MDAMB231细胞,一些肿瘤表现出近乎完全的消退(图4C-E)。这表明抗vegfc治疗,特别是与RT联合使用,可能是限制TNBC进展的有效策略。总之,我们的研究表明,P和X放射治疗在TNBC细胞中产生不同的分子效应,P照射的肿瘤更大,X照射的肿瘤表现出更强的分子特征。这些差异表明,如果耐药细胞存活,X-RT可能导致更严重的复发。未来的研究应侧重于了解这些辐射特异性效应,并制定管理X-RT相关风险的策略。此外,我们的研究强调了抗vegfc治疗的潜力,特别是如果在照射前给药,可以抵消辐射引起的分子变化。对抗vegfc治疗方案的比较临床试验和进一步研究有望推进TNBC的治疗策略。构思与设计:Gilles pag<e:1>和fracimdassic Luciano。方法论的发展:萨哈拉纳兹·萨拉克。数据获取:sarahnaz Sarlak, Delphine Marotte, Alessandra Pierantoni, Jessy siera, mengchen Tsai, Arthur Karaulic和Roxane Sylvestre。数据分析和解释:sarnaz Sarlak, Florent Morfoisse, Barbara Garmy-Susini, fracimdsamric Luciano, Gilles pag<e:1>和Paraskevi Kousteridou。写作、评论:sarnaz Sarlak, Florent Morfoisse, Meng-Chen Tsai, fracei Luciano和Gilles pag<e:1>。行政、技术或物质支持:Marie Vidal, Joël hsamrault和Gilles pag<e:1>。学习指导:frac . Luciano和Gilles . pag<e:1>。作者声明无利益冲突。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
15.90
自引率
1.90%
发文量
450
审稿时长
4 weeks
期刊介绍: Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
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