Tumor deposits in axillary adipose tissue in patients with breast cancer:Do they matter?

Tumor deposits(TDs)are defined as discrete,irregular clusters of tumor cells lying in the soft tissue adjacent to but separate from the primary tumor,and are usually found in the lymphatic drainage area of the primary tumor.By definition,no residual lymph node structure should be identified in these tumor masses.At present,TDs are mainly reported in colorectal cancer,with a few reports in gastric cancer.There are very few reports on breast cancer(BC).For TDs,current dominant theories suggest that these are the result of lymph node metastasis of the tumor with complete destruction of the lymph nodes by the tumor tissue.Even some pathologists classify a TD as two lymph node metastases for calculation.Some pathologists also believe that TDs belong to the category of disseminated metastasis.Therefore,regardless of the origin,TDs are an indicator of poor prognosis.Moreover,for BC,sentinel lymph node biopsy is generally used at present.Whether radical axillary lymph node dissection should be adopted for BC with TDs in axillary lymph nodes is still inconclusive.The present commentary of this clinical issue has certain guiding significance.It is aimed to increase the awareness of the scientific community towards this under-recognized problem in BC pathology.

Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models

Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem,including tumor cells and microenvironment.Breast cancer stem cells(BCSCs)constitute a small population of cancer cells with unique characteristics,including their capacity for self-renewal and differentiation.Studies have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast cancer.The tumor microenvironment(TME),composed of stromal cells,immune cells,blood vessel cells,fibroblasts,and microbes in proximity to cancer cells,is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival,growth,and dissemination,thereby influencing metastatic ability.Hence,a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer metastasis.In this review,we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis,as well as the underlying regulatory mechanisms.Furthermore,we provide an overview of relevant mouse models used to study breast cancer metastasis,as well as treatment strategies and clinical trials addressing BCSC-TME interactions during metastasis.Overall,this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.

Tumor microenvironment: driving forces and potential therapeutic targets for breast cancer metastasis

Distant metastasis to specific target organs is responsible for over 90%of breast cancer?related deaths,but the underlying molecular mechanism is unclear.Mounting evidence suggests that the interplay between breast cancer cells and the target organ microenvironment is the key determinant of organ?specific metastasis of this lethal disease.Here,we highlight new findings and concepts concerning the emerging role of the tumor microenvironment in breast cancer metastasis;we also discuss potential therapeutic intervention strategies aimed at targeting compo?nents of the tumor microenvironment.

A Totally Absorbable Multilayer PLGA Implant Device Containing Doxorubicin Inhibited Tumor Growth and Metastasis without Systemic Toxicity in Murine Breast Cancer and an Ideal Pharmacological Paradigm for Regional Chemotherapy

We hypothesize that a cylinder implant made of multilayer Poly-lactic-co-glycolic-acid (PLGA) membrane can be a method for controlled and extended drug release. We fashioned a multilayer cylindrical implant termed STID100 that released doxorubicin for 3 weeks in an orthotopic 4T1 breast cancer model in Balb/C mice. This implant starts as a thin doxorubicin-embedded PLGA membrane, and is then rolled into a cylinder containing an air gap between the membrane layers. Its controlled sustained release delivered 2× the amount of the intravenous (IV) equivalent of doxorubicin, inhibited the primary tumor, and prevented lung metastasis. Importantly it did not cause weight loss, splenomegaly, or cardiac toxicity vs systemically administrated doxorubicin. This favorable safety profile is further substantiated by the finding of no detectable plasma doxorubicin in multiple time points during the 3-week period, and low tumor doxorubicin concentration. The implant system delivered to the specification of an ideal pharmacological paradigm might offer a better coverage of the local tumor, significantly preventing metastatic spread with less drug toxicity to many vital organs, compared to the traditional pharmacology of IV route. The profile of STID made it an attractive therapeutic alternative in metastatic tumor prevention, pain management and many other diverse clinical scenarios.

Stability and variability of molecular subtypes:comparative analysis of primary and metastatic triple-negative breast cancer

Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Methods:We assembled a large-scale,real-world cohort comprised of 880 TNBC patients[465 early-stage TNBC(eTNBC)and 415 metastatic TNBC(mTNBC)patients]who were treated at Fudan University Shanghai Cancer Center.The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort.Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes.Results:The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1%(47/465).The median overall survival(OS)in the mTNBC cohort was 27.2 months[95%confidence interval(CI),24.4–30.2 months],which indicated a poor prognosis.The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed.Consistent molecular subtypes were maintained in 77.5%of the patients throughout disease progression with the mesenchymal-like(MES)subtype demonstrating a tendency for subtype transition and brain metastasis.Additionally,a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial.Conclusions:Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression.However,we emphasize the major importance of repeat pathologic confirmation of the MES subtype.

Role of platelets and breast cancer stem cells in metastasis

The high mortality rate of breast cancer is mainly caused by the metastatic ability of cancer cells,resistance to chemotherapy and radiotherapy,and tumor regression capacity.In recent years,it has been shown that the presence of breast cancer stem cells is closely associated with the migration and metastatic ability of cancer cells,as well as with their resistance to chemotherapy and radiotherapy.The tumor microenvironment is one of the main molecular factors involved in cancer and metastatic processes development,in this sense it is interesting to study the role of platelets,one of the main communicator cells in the human body which are activated by the signals they receive from the microenvironment and can generate more than one response.Platelets can ingest and release RNA,proteins,cytokines and growth factors.After the platelets interact with the tumor microenvironment,they are called"tumor-educated platelets."Tumor-educated platelets transport material from the tumor microenvironment to sites adjacent to the tumor,thus helping to create microenvironments conducive for the development of primary and metastatic tumors.It has been observed that the clone capable of carrying out the metastatic process is a cancer cell with stem cell characteristics.Cancer stem cells go through a series of processes,including epithelial-mesenchymal transition,intravasation into blood vessels,movement through blood vessels,extravasation at the site of the establishment of a metastatic focus,and site colonization.Tumor-educated platelets support all these processes.

The Role of Body Composition Analyzer in the Preoperative Assessment of Breast Cancer Patients

Background: The segmental multi-frequency bioelectrical impedance analysis (SMF-BIA) is a useful method for evaluating physical health and nutritional status in various clinical settings. But less is known about its role in the preoperative assessment of breast cancer patients. Herein, we try to monitor the changes in body composition of preoperative patients by SMF-BIA and figure out its association with clinical features. Methods: The changes in body composition were monitored by SMF-BIA in 563 female patients with breast cancer. Monitor body moisture and collect relevant data on the day before surgery as a prospective study. Retrospective analysis will be conducted based on preoperative data and pathological results after lymph node resection, Spearman’s correlation coefficients were calculated to investigate the correlation among parameters. Results: We found that the body water, extracellular water ratio, and bioelectrical impedance of the affected upper limbs of patients with different tumor stages or different numbers of lymph node metastases were significantly different from those of their healthy upper limbs (P P P P P Conclusion: SMF-BIA can help monitor the changes in body composition of breast cancer patients and provide detailed information for making a personalized treatment plan and individual nursing schedule. However, the value of SMF-BIA in preoperative assessment still needs to be validated in large prospective clinical trials.

Prognostic role of tumor budding in breast cancer

Tumor budding, defined as a small number of cancer cells observed in pathology sections detached from the main tumor mass, is a common phenomenon in cancer. It issuggested that cells in buds are in the process of actively moving away from the primary tumor in the first step of metastasis. Tumor budding has been observed in a variety of carcinomas and is best studied in colorectal cancers where it portends poor prognosis. More recently, tumor budding was found to be of prognostic significance in other cancers including breast cancer. Tumor budding in breast cancer is associated with other adverse pathologic factors, such as larger tumor size and lymphovascular invasion, but may have additional independent prognostic value. In the future, standardization of the quantification criteria for tumor budding may further aid in its adoption as a prognostic marker.

Successful treatment of breast metastasis from primary transverse colon cancer:A case report

BACKGROUND The incidence of colon cancer is increasing worldwide.Treatments for colon cancer include surgery and surgery combined with chemotherapy and radiotherapy,but the median survival rate is still poor.Colon cancer most commonly metastasizes to the lymph nodes,lungs,liver,peritoneum,and brain,but breast metastasis is rare.There is no agreement on its treatment.CASE SUMMARY A 23-year-old woman was admitted to our hospital for further treatment with a history of acute abdominal pain,nausea,and vomiting.Her physical examination and computed tomography scan revealed an abdominal tumor.Transverse colectomy was successfully performed.Histopathological examination revealed that the tumor was a mucosecretory adenocarcinoma with signet ring cells.The patient inadvertently found a mass in the outer upper quadrant of the right breast after four cycles of XELOX chemotherapy[oxaliplatin 130 mg/m^(2),d1,intravenous(iv)drip for 2 h;capecitabine 1000 mg/m^(2),po,bid,d1–d14].After discussion with the patient,we performed a lumpectomy and frozen biopsy.The latter revealed that the breast tumor was intestinal metastasis.Genetic testing showed wild-type RAS and BRAF.So we replaced the original chemotherapy with FOLFIRI[irinotecan 180 mg/m^(2),d1,iv drip for 3–90 min;leucovorin 400 mg/m^(2),d1,iv drip for 2 h;5-fluorouracil(5-FU)400 mg/m^(2),d1 and 5-FU 1200 mg/(m^(2)d)×2 d,continuous iv drip for 46–48 h]+cetuximab(500 mg/m^(2),d1,iv drip for 2 h).Serum levels of tumor markers returned to normal after several treatment cycles,and there was no evidence of tumor recurrence or metastasis.CONCLUSION Breast metastasis from colon cancer is rare.Radical breast surgery should be avoided unless needed for palliation.Chemotherapy combined with targeted therapy should be the first choice.

Understanding the function of the tumor microenvironment,and compounds from marine organisms for breast cancer therapy

The pathology and physiology of breast cancer(BC),including metastasis,and drug resistance,is driven by multiple signaling pathways in the tumor microenvironment(TME),which hamper antitumor immunity.Recently,long non-coding RNAs have been reported to mediate pathophysiological developments such as metastasis as well as immune suppression within the TME.Given the complex biology of BC,novel personalized therapeutic strategies that address its diverse pathophysiologies are needed to improve clinical outcomes.In this review,we describe the advances in the biology of breast neoplasia,including cellular and molecular biology,heterogeneity,and TME.We review the role of novel molecules such as long non-coding RNAs in the pathophysiology of BC.Finally,we provide an up-to-date overview of anticancer compounds extracted from marine microorganisms,crustaceans,and fishes and their synergistic effects in combination with other anticancer drugs.Marine compounds are a new discipline of research in BC and offer a wide range of anti-cancer effects that could be harnessed to target the various pathways involved in BC development,thus assisting current therapeutic regimens.

Effects of Notch-1 Down-regulation on Malignant Behaviors of Breast Cancer Stem Cells

This study examined the effect of Notch-1 signaling on malignant behaviors of breast cancer cells by regulating breast cancer stem cells （BCSCs）. BCSCs were enriched by using serum-free me- dium and knocked out of Notch-1 by using a lentiviral vector. Real-time polymerase chain reaction （RT-PCR） and Western blotting were used to detect the Notch-1 expression levels in breast cancer cell lines and BCSCs, and fl0w cytometry to detect the proportion of BCSCs in BCSC spheres. The BCSC self-renewal, migration, invasion, and tumorigenicity were examined by the tumor microsphere-forming assay and transwell assay and after xenotransplantation. The results showed that the Notch-1 silencing reduced the number of BCSC spheres, the proportion of BCSCs, and the number of cells penetrating through the transwell membrane. It also decreased the size of tumors that were implanted in the nude mice. These results suggest that Notch-1 signaling is intimately linked to the behaviors of BCSCs. Blocking Notch-1 signaling can inhibit the malignant behaviors of BCSCs, which may provide a prom- ising therapeutical approach for breast cancer.

A Biliary Recurrence of a Breast Cancer: Case Report and Review of the Literature

A 51-year-old female with a history of radical mastectomy with axillary lymph node dissection, adjuvant chemotherapy and radiation for a breast cancer was referred to the emergency room due to cholangitis. A CT scan showed a common bile duct mass invading the duodenum. After bile draining, the investigations led to an undifferentiated carcinoma with positive hormonal receptors. The diagnosis of a breast cancer recurrence was established and the patient was commenced on taxane therapy.

Gastrointestinal metastasis secondary to invasive lobular carcinoma of the breast:A case report

BACKGROUND Gastrointestinal metastasis of breast cancer is rare,and clinicians may not have previously encountered this disease in clinical practice.CASE SUMMARY We report a patient with invasive lobular carcinoma of the breast who developed gastrointestinal metastasis two years after modified radical surgery.Mild elevation of carbohydrate antigen 15-3 was observed in the patient at an early stage;however,diagnosis and treatment were delayed due to non-specific clinical manifestations and no identifiable metastasis observed on imaging.CONCLUSION Clinicians should pay attention to gastrointestinal metastasis of breast cancer,especially invasive lobular carcinoma of the breast.

Expression of Tyrosine Kinase Syk in Breast Cancer and Their Clinical Significance

Objective: To evaluate the effects of the Syk mRNA expression in human breast cancer on tumor growth and metastasis,and the correlation of the Syk gene expression with ER,PR,P53,and HER2/neu. Methods:Using semi-RT-PCR,specimens from 40 breast cancer patients(tumor tissues,adjacent normal tissues),and 15 fibroadenoma were detected for the expression of the Syk gene and level of Syk mRNA.Meanwhile,ER,PR,P53,HER2/neu were detected in 40 tumor tissues from breast cancer with immunohistochemical staining. Results:Expression of the Syk gene was detected in all normal breast tissues.Unlike normal breast tissue,31 out of 40 breast cancer tissues did not show any detectable Syk mRNA expression,and there were significant differences in two groups(P<0.05).The level of Syk mRNA in the primary breast cancer tissues was significantly lower than that in the adjacent non-cancerous breast tissues and benign fibroadenoma breast tissues(P<0.05).Furthermore,only two breast cancer tissues in 18 patients with lymph node metastasis had the Syk mRNA expression.The Syk mRNA expression was negatively correlated to lymph node metastasis,HER2/neu protein expression(P<0.05). Conclusion: The expression of the Syk gene may play an important role in suppressing growth and metastasis of breast cancer.

Tumor-Specific Histo-Blood Group Antigens: Apropos of Two Cases

Cancer cells with immunogenic properties having altered protein glycosylation, modified blood group substances have been widely studied. Due to the genetic instability occurring during carcinogenesis the glycosyltransferases may suffer from posttranslation sequence modification. The author describes 2 autopsy cases, where in the background of the unusual metastatic tumor presentation, incompatible blood group antigenic determinants have been demonstrated using blood group specific lectins and monoclonal antibodies (mAb). In the first case, reported here, a 10-year-old girl developed an acute myeloid leukemia and died in a septic endotoxin shock after successful cytostatic treatment of a juvenile signet ring cell cancer of her colon. At autopsy there were no signs of tumor except bilateral apple-sized mucinous ovarian (Krukenberg) metastases. While she had erythrocyte phenotype of blood group A, the signet ring adenocarcinoma cells expressed blood group B incompatible antigenic determinants with lectin/mAb. In the second case, the autopsy of a 78-year-old female resulted in no macroscopic tumor sign except a moderately enlarged, ham hard spleen. Light microscopy revealed adenocarcinomatous infiltration in the splenic sinusoids. The patient had blood group O, while the metastatic cells in the spleen reacted with Breast Carcinoma Antigen (BioGenex) and incompatible anti-B Banderiaeasimplicifolia agglutinin I and anti-B mAb. It proved to be a case of an occult, completely regressed breast cancer. Based on these observations the expression of tumor specific incompatible blood group antigens might occur from time to time, mostly in adenocarcinomas. Accordingly, blood group-based specific immuno-oncotherapy could be considered in some cancer cases.

乳腺癌脑转移分子机制的研究进展

乳腺癌(BC)是女性最常见的恶性肿瘤之一,其发病率和死亡率在全球大多数国家女性肿瘤中排名第一。BC患者的高死亡率与骨、肺、脑和肝等远端器官的复发和转移有关。目前已知乳腺癌发生脑转移的有关信号通路有PI3K/Akt/mTOR通路、Wnt/β-catenin通路、RAS/ERK通路、EGFR通路、STAT3通路、NF-κB通路、ROS/NF-κB通路及PDGFB/PDGFR-β通路。此外,有关研究发现外泌体、非编码RNA以及代谢成分等物质可通过破坏血脑屏障、协助建立脑转移微环境来参与乳腺癌的脑转移。本文对乳腺癌脑转移的可能分子机制和信号通路进行综述,旨在为乳腺癌脑转移的精准靶向治疗提供新思路。

临床病理特征结合SWE参数对乳腺癌腋窝淋巴结转移的预测价值

目的探讨临床病理特征结合剪切波弹性成像(SWE)参数对乳腺癌腋窝淋巴结转移的预测价值。方法将本院收治的72例乳腺癌患者均行SWE检查、同侧腋窝淋巴结清扫或前哨淋巴结活检。根据腋窝淋巴结是否发生转移分为未转移组39例与转移组33例。采用单因素及多因素Logistic分析腋窝淋巴结转移的风险因素。采用ROC曲线评估临床病理特征联合SWE对腋窝淋巴结转移的诊断效能。结果单因素分析结果显示,两组组织学分级、淋巴管血管侵犯、病灶微钙化、Ki-67、淋巴结最大纵径、淋巴结最大横径、淋巴结皮质厚度、弹性模量平均值(E mean)、弹性模量最大值(E max)及弥散度(SD)比较,差异有显著性(P<0.05)。多因素Logistic回归结果显示,淋巴管血管侵犯、组织学分级(Ⅲ级)、E max及SD为乳腺癌患者发生腋窝淋巴结转移的危险因素(P<0.05)。ROC结果显示,组织学分级为Ⅲ级、存在淋巴管血管侵犯、E max≥45.635 kPa、SD≥8.450的联合预测效能高于各指标单独预测效能。结论临床病理特征结合SWE参数对乳腺癌腋窝淋巴结转移具有一定的预测价值。

白藜芦醇抗乳腺癌的研究进展

乳腺癌的发病率在女性恶性肿瘤中高居榜首,具有侵袭性强、恶性程度高、预后差的特征。白藜芦醇是一种植物抗氧化剂,在对抗乳腺癌发生和发展中具有潜在的多效性。本文通过评估多个体外和体内研究以探索白藜芦醇干预乳腺癌的作用机制,发现白藜芦醇可通过诱导细胞凋亡,调控自噬,抑制糖酵解,调节肿瘤微环境、基质金属蛋白酶、上皮-间质转化、耐药蛋白等的表达,来削弱乳腺癌细胞的增殖和存活能力,抑制乳腺癌细胞的生长、转移和侵袭,逆转乳腺癌细胞对阿霉素的耐药。白藜芦醇的临床试验研究数量有限,主要是关于其对乳腺癌的预防作用,这可能是影响全面评估白藜芦醇抗癌效果的原因之一。

B7同源物4分子对乳腺癌细胞miRNA表达谱的影响

目的通过解析免疫调控分子B7同源物4(B7-H4)对乳腺癌miRNA表达谱的影响,探讨B7-H4介导肿瘤免疫逃逸和乳腺癌进展的潜在机制.方法采用miRNA测序分析B7-H4敲除或过表达的乳腺癌细胞系,筛选共同的差异miRNA;通过qRT-PCR验证差异miRNA,采用TargetFinder和TargetScan预测差异miRNA的靶基因,同时进行基因本体(GO)和京都基因与基因组百科全书数据库(KEGG)信号通路的富集;采用Kaplan-Meier plotter对关键miRNA及靶基因进行生存分析.结果B7-H4敲除后有415个miRNA发生显著变化,而过表达后有134个差异miRNA,通过叠加筛选到36个共同的差异miRNA,通过qRT-PCR验证筛选获得14个差异miRNA;对其进行下游靶基因预测,得到TP53AIP1、RAD52、CDH7、FOXA1、CDH2和ZEB1等涉及细胞增殖和转移功能的基因;富集分析发现,靶基因主要参与癌症进展相关的MAPK和Ras信号通路等,推测其可能参与乳腺癌的病理进展.结论B7-H4通过参与乳腺癌miRNA的表观调控,影响关键靶基因的表达,介导细胞增殖和转移,影响乳腺癌的进展.

Self-assembly of CXCR4 antagonist peptide-docetaxel conjugates for breast tumor multi-organ metastasis inhibition

As a representative chemotherapeutic drug,docetaxel(DTX)has been used for breast cancer treatment for decades.However,the poor solubility of DTX limits its efficacy,and the DTX based therapy increases the metastasis risk due to the upregulation of C-X-C chemokine receptor type 4(CXCR4)expression during the treatment.Herein,we conjugated CXCR4 antagonist peptide(CTCE)with DTX(termed CTCE-DTX)as an anti-metastasis agent to treat breast cancer.CTCE-DTX could selfassemble to nanoparticles,targeting CXCR4-upregulated metastatic tumor cells and enhancing the DTX efficacy.Thus,the CTCE-DTX NPs achieved promising efficacy on inhibiting both bonespecific metastasis and lung metastasis of triple-negative breast cancer.Our work provided a rational strategy on designing peptide-drug conjugates with synergistic anti-tumor efficacy.