The Contribution of Cholesterol and Its Metabolites to the Pathophysiology of Breast Cancer

As the most common cancer in women, one in eight will develop invasive breast cancer over their lifetime making it the second most common cause of cancer-related death among women. Of the many known risk factors for developing breast cancer, obesity stands out as prominent and modifiable. Interestingly, elevated cholesterol is highly associated with obesity and has emerged as an independent risk factor for breast cancer onset and recurrence. This indicates that cholesterol also contributes to the breast cancer pathogenicity of obesity. This review highlights our current understanding of the mechanisms by which cholesterol impacts breast cancer. Key preclinical studies have been highlighted, including the discussion of homeostatic control of cholesterol levels, signaling by cholesterol metabolites through the estrogen receptors, cholesterol formation of lipid rafts and subsequent signaling, and the potential roles of cholesterol in creating a pro-inflammatory tumor microenvironment. Future directions and avenues for therapeutic exploitation are also considered.     

Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance

Breast cancer has been shown to live in the tumor microenvironment,which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells.Diverse components of the breast cancer microenvironment,such as suppressive immune cells,re-programmed fibroblast cells,altered extracellular matrix (ECM) and certain soluble factors,synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis.Among these components,stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways,whereas the ECM features biochemical and biomechanical changes.However,triple-negative breast cancer (TNBC),the most aggressive subtype of this disease that lacks effective therapies available for other subtypes,is considered to feature a unique microenvironment distinct from that of other subtypes,especially compared to Luminal A subtype.Because these changes are now considered to significantly impact breast cancer development and progression,these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC.In this review,we focus on the composition of the TNBC microenvironment,concomitant distinct biological alteration,specific interplay between various cell types and TNBC cells,and the prognostic implications of these findings.     

单细胞测序技术在乳腺癌研究中的应用进展

乳腺癌是全球女性发病率最高的恶性肿瘤,也是女性癌症相关致死的主要原因之一。乳腺癌是一种高度异质性的疾病,肿瘤间异质性和肿瘤内异质性使得精准分型治疗工作进展缓慢。传统高通量测序技术在乳腺癌研究中的应用已为揭示乳腺癌的发生、发展、驱动基因、精确分型、诊断及治疗方面提供了重要参考,但仍有局限性,无法揭示肿瘤内异质性。近年来兴起的单细胞测序技术在灵敏度、准确度和效率方面都得到了极大的提高,研究人员可以分析复杂混合细胞中的单个细胞的分子生物学信息,该技术在研究肿瘤异质性方面展现出极大的优越性。近年来,单细胞测序技术在乳腺癌研究中的应用已有多项重要研究成果发表,包括从单细胞层面解析乳腺癌转录组图谱、探索乳腺癌微环境异质性、探索乳腺癌耐药发生机制、探索乳腺癌克隆异质性及克隆演化研究,以及综合挖掘单细胞公共数据资源揭示乳腺癌异质性。本文对近年来单细胞测序技术在乳腺癌中的应用相关前沿重要研究进行综述并深入思考,旨在为乳腺癌研究者应用单细胞测序技术提供参考,促进单细胞测序技术在乳腺癌研究中的广泛应用。     

Adaptation of energy metabolism in breast cancer brain metastases

Brain metastases are among the most feared complications in breast cancer, as no therapy exists that prevents or eliminates breast cancer spreading to the brain. New therapeutic strategies depend on specific knowledge of tumor cell properties that allow breast cancer cell growth within the brain tissue. To provide information in this direction, we established a human breast cancer cell model for brain metastasis based on circulating tumor cells from a breast cancer patient and variants of these cells derived from bone or brain lesions in immunodeficient mice. The brain-derived cells showed an increased potential for brain metastasis in vivo and exhibited a unique protein expression profile identified by large-scale proteomic analysis. This protein profile is consistent with either a selection of predisposed cells or bioenergetic adaptation of the tumor cells to the unique energy metabolism of the brain. Increased expression of enzymes involved in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation pathways suggests that the brain metastatic cells derive energy from glucose oxidation. The cells further showed enhanced activation of the pentose phosphate pathway and the glutathione system, which can minimize production of reactive oxygen species resulting from an enhanced oxidative metabolism. These changes promoted resistance of brain metastatic cells to drugs that affect the cellular redox balance. Importantly, the metabolic alterations are associated with strongly enhanced tumor cell survival and proliferation in the brain microenvironment. Thus, our data support the hypothesis that predisposition or adaptation of the tumor cell energy metabolism is a key element in breast cancer brain metastasis, and raise the possibility of targeting the functional differentiation in breast cancer brain lesions as a novel therapeutic strategy.     

The tumor microenvironment

The concept of the tumor microenvironment, developed from Paget's "seed and soil" theory is made up of the cancer cells, the stromal tissue, and the extracellular matrix. In this mini-review, each of the components of this dynamic network will be examined. We will show that there are a multitude of complex interactions and a host of molecules involved in tumorogenesis and metastasis. We will further illustrate this notion with examples from the tumor microenvironment of breast cancer. Lastly, we conclude with thoughts about how this will influence the surgical field with examples of therapeutic agents already in use that target aspects of this microenvironment.     

乳腺肿瘤微环境靶向治疗的研究进展

肿瘤细胞周围的免疫细胞、成纤维细胞、内皮细胞及其驱动分子等组成的肿瘤微环境可以调控肿瘤细胞的生长、侵袭和转移,因此在针对肿瘤细胞进行治疗的同时靶向肿瘤微环境成为乳腺癌综合治疗的新策略。对乳腺肿瘤微环境中的预测标志物,以及如何靶向肿瘤微环境增加抗乳腺肿瘤治疗的疗效进行了综述,为乳腺癌的治疗提供新的思路。     

Calsequestrin 2 overexpression in breast cancer increases tumorigenesis and metastasis by modulating the tumor microenvironment

The spatial tumor shape is determined by the complex interactions between tumor cells and their microenvironment. Here, we investigated the role of a newly identified breast cancer‐related gene, calsequestrin 2 (CASQ2), in tumor–microenvironment interactions during tumor growth and metastasis. We analyzed gene expression and three‐dimensional tumor shape data from the breast cancer dataset of The Cancer Genome Atlas (TCGA) and identified CASQ2 as a potential regulator of tumor–microenvironment interaction. In TCGA breast cancer cases containing information of three‐dimensional tumor shapes, CASQ2 mRNA showed the highest correlation with the spatial tumor shapes. Furthermore, we investigated the expression pattern of CASQ2 in human breast cancer tissues. CASQ2 was not detected in breast cancer cell lines in vitro but was induced in the xenograft tumors and human breast cancer tissues. To evaluate the role of CASQ2, we established CASQ2‐overexpressing breast cancer cell lines for in vitro and in vivo experiments. CASQ2 overexpression in breast cancer cells resulted in a more aggressive phenotype and altered epithelial–mesenchymal transition (EMT) markers in vitro. CASQ2 overexpression induced cancer‐associated fibroblast characteristics along with increased hypoxia‐inducible factor 1α (HIF1α) expression in stromal fibroblasts. CASQ2 overexpression accelerated tumorigenesis, induced collagen structure remodeling, and increased distant metastasis in vivo. CASQ2 conferred more metaplastic features to triple‐negative breast cancer cells. Our data suggest that CASQ2 is a key regulator of breast cancer tumorigenesis and metastasis by modulating diverse aspects of tumor–microenvironment interactions.     

Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

Among all cancers, malignancies of the breast are the second leading cause of cancer death in the United States after carcinoma of the lung. One of the major factors considered when assessing the prognosis of breast cancer patients is whether the tumor has metastasized to distant organs. Although the exact phenotype of the malignant cells responsible for metastasis and dormancy is still unknown, growing evidence has revealed that they may have stem cell-like properties that may account for resistance to chemotherapy and radiation. One process that has been attributed to primary tumor metastasis is the epithelial-to-mesenchymal transition. In this review, we specifically discuss breast cancer dissemination to the bone marrow and factors that ultimately serve to shelter and promote tumor growth, including the complex relationship between mesenchymal stem cells (MSCs) and various aspects of the immune system, carcinoma-associated fibroblasts, and the diverse components of the tumor microenvironment. A better understanding of the journey from the primary tumor site to the bone marrow and subsequently the oncoprotective role of MSCs and other factors within that microenvironment can potentially lead to development of novel therapeutic targets.     

Tumor microenvironment and breast cancer progression: a complex scenario

It is now widely accepted that the development and progression of a tumor toward the malignant phenotype is highly dependent on interactions between tumor cells and the tumor microenvironment. Different components of the tumor microenvironment may have stimulatory or inhibitory effects on tumor progression by regulating the gene expression repertoire in tumor cells and stromal cells. This review analyzes novel research findings on breast cancer progression, discussing acquisition of the metastatic phenotype in breast disease in relation to different aspects of cross-talk among components of the tumor microenvironment. Knowledge of the interaction of all of these factors would contribute to elucidating the mechanisms that disrupt regulatory/signaling cascades and downstream effects in breast cancer.     

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 components of the tumor microenvironment.     

Stromal cells in tumor microenvironment and breast cancer

Cancer is a systemic disease encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion, and metastasis. In breast cancer, CAFs not only promote tumor progression but also induce therapeutic resistance. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistance. This review summarizes the current understandings of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. In addition, the effects of other stromal components such as endothelial cells, macrophages, and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to categorize patients into a specific and confirmed subtype for personalized treatment.     

Managing bone complications of solid tumors

Bone metastases are a common occurrence in patients with breast cancer, lung cancer and prostate cancer. Bone metastases cause considerable morbidity including pain, impaired mobility, pathologic fracture, spinal cord or nerve root compression, bone marrow infiltration and hypercalcemia of malignancy. These complications result from the derangement of normal bone metabolism that arise from interactions between factors originating in tumor cells and others originating in the microenvironment of the bone. Fortunately, there is an increasing array of treatment options for the skeletal complications associated with bone metastases arising from breast, lung, and prostate cancer. The goals of treatment for such skeletal complications are to relieve pain and reduce the risk of fracture. Traditional therapies to treat skeletal malignancies include radiation, surgery, and chemotherapy. In recent years, bisphosphonates have become the treatment of choice because of their ability to reduce bone resorption, leading to decreases in hypercalcemia, new osteolytic lesions, and fractures, thereby ameliorating pain and improving quality of life.     

Splenectomy reduces lung metastases and tumoral and metastatic niche inflammation

The immune microenvironment plays a crucial role in supporting tumor growth and metastasis. Tumor-associated macrophages (TAMs) and neutrophils (TANs) are essential components of this microenvironment and affect tumor growth and progression in almost all solid neoplasms. Furthermore, TAMs, TANs and tumor-infiltrating dendritic cells (TIDCs) are found to infiltrate specific distant organs to prepare them as a site for metastatic cell seeding, forming the pre-metastatic niche. The spleen was identified as a major reservoir and source of circulating and tumor infiltrating immune cells. However, discrepancies about its role in supporting tumor growth exist. Thus, here we investigated the role of splenectomy in primary tumor and metastatic growth, and in the formation of an inflammatory niche. In a murine 4T1 and E0771 breast and Panc02 pancreatic cancer model, our results show that while splenectomy reduces the number of infiltrating TAMs, TANs and TIDCs within primary tumors, it does not affect its growth. In line, fewer TAMs, TANs and TIDCs accumulate in the metastatic microenvironment after splenectomy. Interestingly though, this affected metastatic growth depending on the metastatic route/site. The number of hematogenous breast cancer lung metastases was reduced after splenectomy but no effect was observed in breast or pancreatic lymph node metastases. Moreover, we observed that the immune composition of the pre-metastatic niche in lungs of breast cancer bearing mice was altered, and that this could cause the reduction of metastases. Altogether, our results highlight that splenectomy affects the immune microenvironment not only of primary tumors but also of pre-metastatic and metastatic sites.     

Controversial role of mast cells in breast cancer tumor progression and angiogenesis

Breast cancer is a neoplastic disease and is a cause of cancer-related mortality for women. Among cellular and molecular regulators of the microenvironment, mast cells and vascular endothelial growth factor (VEGF), are correlated with tumor progression and prognosis in breast cancer. Clinical and experimental studies on breast cancer have revealed a marked correlation between increased angiogenesis, metastasization, and poorer prognosis. After a brief introduction on angiogenesis evidence and angiogenic factors role in different breast cancer subtypes, in this article, we have discerned the relationship between mast cell infiltration, angiogenesis, and tumor progression in human breast cancer with particular reference to the dual role of mast cells, in terms of both pro- or anti-tumoral activity and poor or good biomarker.     

Pattern response of dendritic cells in the tumor microenvironment and breast cancer

Breast cancer (BC) is the most common malignant neoplasm and the cause of death by cancer among women worldwide. Its development, including malignancy grade and patient prognosis, is influenced by various mutations that occur in the tumor cell and by the immune system’s status, which has a direct influence on the tumor microenvironment and, consequently, on interactions with non-tumor cells involved in the immunological response. Among the immune response cells, dendritic cells (DCs) play a key role in the induction and maintenance of anti-tumor responses owing to their unique abilities for antigen cross-presentation and promotion of the activation of specific lymphocytes that target neoplasic cells. However, the tumor microenvironment can polarize DCs, transforming them into immunosuppressive regulatory DCs, a tolerogenic phenotype which limits the activity of effector T cells and supports tumor growth and progression. Various factors and signaling pathways have been implicated in the immunosuppressive functioning of DCs in cancer, and researchers are working on resolving processes that can circumvent tumor escape and developing viable therapeutic interventions to prevent or reverse the expression of immunosuppressive DCs in the tumor microenvironment. A better understanding of the pattern of DC response in patients with BC is fundamental to the development of specific therapeutic approaches to enable DCs to function properly. Various studies examining DCs immunotherapy have demonstrated its great potential for inducing immune responses to specific antigens and thereby reversing immunosuppression and related to clinical response in patients with BC. DC-based immunotherapy research has led to immense scientific advances, both in our understanding of the anti-tumor immune response and for the treatment of these patients.     

Microenvironment and endocrine resistance in breast cancer: Friend or foe?

Breast cancer affects one in eight women around the world. Seventy five percent of these patients have tumors that are estrogen receptor positive and as a consequence receive endocrine therapy. However, about one third eventually develop resistance and cancer reappears. In the last decade our vision of cancer has evolved to consider it more of a tissue-related disease than a cell-centered one. This editorial argues that we are only starting to understand the role the tumor microenvironment plays in therapy resistance in breast cancer. The development of new therapeutic strategies that target the microenvironment will come when we clearly understand this extremely complicated scenario. As such, and as a scientific community, we have extremely challenging work ahead. We share our views regarding these matters.     

Tumor microenvironment and progression

Tumor blood vessels are heterogeneous, of at least six distinct types, are induced primarily by vascular endothelial growth factor-A (VEGF-A), and provide a potentially useful therapeutic target. Breast cancer is characterized by changes in the microenvironment that result in altered tensional homeostasis. Also, breast cancers arise as the result of epigenetic as well as genetic changes. Tumor blood vessel pericytes result, in part, from bone marrow precursor cells, and VEGF is a negative regulator of glioblastoma tumor cell invasion.     

B7-H3的作用机制及其在非小细胞肺癌中的研究新进展

肺癌是目前世界上癌症相关性死亡的主要原因之一。其中最常见的类型为非小细胞肺癌（non-small cell lung cancer,NSCLC）。肺癌患者预后不佳,因此探索新型治疗方案对提高患者预后来说是非常必要的。据研究,共刺激分子B7-H3（CD276）在抗肿瘤免疫中起着重要的作用,而免疫系统的调节机制在抑制肿瘤微环境中的抗肿瘤T细胞介导的免疫反应中起着重要作用。本文阐述了B7-H3的作用机制及其在非小细胞肺癌微环境中表达的临床意义。