Tumor Angiogenesis: Pericytes and Maturation Are Not to Be Ignored

Angiogenesis, an essential component of tumor growth and survival, is regulated by complex interactions between several cell types and soluble mediators. Heterogeneous tumor vasculature originates from the collective effect of the nature of carcinoma and the complexity of the angiogenic network. Although the application of angiogenesis inhibitors in some types of cancers has shown clinical benefits, predictive markers to assess treatment effects have yet to be established. In this review, we focus on tumor vessel maturity as a potential marker for evaluating treatment response

Risk reduction of distant metastasis in hormone-sensitive postmenopausal breast cancer

Adjuvant endocrine therapy remains the principle strategy to reduce recurrence risk in postmenopausal women with early breast cancer. Studies of the natural history of breast cancer have shown that, while not reaching zero at any time point, the risk of recurrence is highest in the first 5 years following initial diagnosis and treatment. Within this initial 5 years, there is a peak of recurrence at the 2- to 3-year mark. Among the types of breast cancer recurrences observed at this early peak, distant metastasis (DM) predominates over local or contralateral relapse. DM recurrences are most strongly linked to breast-cancer-related death, and it has been suggested that adjuvant endocrine therapies that are most effective in minimizing the early peak of DM recurrence may have the most favorable impact on survival in women with early breast cancer. Aromatase inhibitors (AIs) including anastrozole, letrozole, and exemestane have gained popularity in the past few years as alternatives to 5 years of adjuvant tamoxifen, the previous standard of care. However, clinicians have not yet resolved how best to integrate AIs into breast cancer treatment; both upfront therapy (i.e., in lieu of tamoxifen) and a sequential/switch strategy (i.e., after some period of prior tamoxifen) have been proposed. The benefits and drawbacks of these approaches to AI treatment, particularly with respect to reducing early DM recurrences, are reviewed

Prognostic factors for survival after first recurrence in breast cancer: a retrospective analysis of 252 recurrent cases at a single institution.

[Introduction]Previous studies have shown that primary breast cancer patients with estrogen receptor (ER)-positive status have better outcomes in terms of both overall survival and disease-free intervals (DFI). However, 25.2 % of our ER-positive patients experienced recurrence. This study aimed to define factors potentially predicting survival after first recurrence in surgically treated patients with stage I–III breast cancer. [Methods]We retrospectively analyzed 252 females with recurrent breast cancer who had undergone surgery and been followed at Kyoto University Hospital in Japan. Age, clinical stage, pathological stage, axillary lymph node involvement, ER status at the time of diagnosis, progesterone receptor status, human epidermal growth factor receptor 2 status, operative method, adjuvant chemotherapy, adjuvant endocrine therapy, use of trastuzumab after recurrence, site of recurrence, DFI, and time of recurrence were examined for possible influences on survival after the first recurrence. [Results]Positive ER status and positive PR status at the time of diagnosis were significantly favorable factors of survival after first recurrence for patients with recurrence, p < 0.001 and p = 0.021, respectively. More than two sites of recurrence (p < 0.001) were associated with shorter survival time after the first recurrence on multivariate analysis. Survival of patients with recurrent breast cancer steadily improved from 1980–1994 to 1995–2008, significantly in ER-negative subgroups. [Conclusions]Positive ER status at the time of diagnosis is a powerful predictor for favorable survival after first recurrence. Survival time after first recurrence of breast cancer has steadily increased in recent decades. Advances in treatments and attitudes about breast cancer have contributed to this improvement in survival after first recurrence

Linear ubiquitination‐induced necrotic tumor remodeling elicits immune evasion

Tumor-elicited inflammation confers tumorigenic properties, including cell death resistance, proliferation, or immune evasion. To focus on inflammatory signaling in tumors, we investigated linear ubiquitination, which enhances the nuclear factor-κB signaling pathway and prevents extrinsic programmed cell death under inflammatory environments. Here, we showed that linear ubiquitination was augmented especially in tumor cells around a necrotic core. Linear ubiquitination allowed melanomas to tolerate the hostile tumor microenvironment and to extend a necrosis-containing morphology. Loss of linear ubiquitination resulted in few necrotic lesions and growth regression, further leading to repression of innate anti-PD-1 therapy resistance signatures in melanoma as well as activation of interferon responses and antigen presentation that promote immune-mediated tumor eradication. Collectively, linear ubiquitination promotes tumor-specific tissue remodeling and the ensuing immune evasion

Cellular senescence triggers intracellular acidification and lysosomal pH alkalinized via ATP6AP2 attenuation in breast cancer cells

がん治療薬による乳がん細胞の老化とpH調整の解明 --新規細胞老化のメカニズム解明に貢献--. 京都大学プレスリリース. 2023-11-27.Several chemotherapeutic drugs induce senescence in cancer cells; however, the mechanisms underlying intracellular pH dysregulation in senescent cells remain unclear. Adenosine triphosphatase H+ transporting accessory protein 2 (ATP6AP2) plays a critical role in maintaining pH homeostasis in cellular compartments. Herein, we report the regulatory role of ATP6AP2 in senescent breast cancer cells treated with doxorubicin (Doxo) and abemaciclib (Abe). A decline in ATP6AP2 triggers aberrant pH levels that impair lysosomal function and cause immune profile changes in senescent breast cancer cells. Doxo and Abe elicited a stable senescent phenotype and altered the expression of senescence-related genes. Additionally, senescent cells show altered inflammatory and immune transcriptional profiles due to reprogramming of the senescence-associated secretory phenotype. These findings elucidate ATP6AP2-mediated cellular pH regulation and suggest a potential link in immune profile alteration during therapy-induced senescence in breast cancer cells, providing insights into the mechanisms involved in the senescence response to anticancer therapy

SALL4 - KHDRBS3 network enhances stemness by modulating CD44 splicing in basal-like breast cancer

Understanding the mechanism by which cancer cells enhance stemness facilitates cancer therapies. Here, we revealed that a stem cell transcription factor, SALL4, functions to enhance stemness in basal‐like breast cancer cells. We used shRNA‐mediated knockdown and gene overexpression systems to analyze gene functions. To evaluate stemness, we performed a sphere formation assay. In SALL4 knockdown cells, the sphere formation ability was reduced, indicating that SALL4 enhances stemness. CD44 is a membrane protein and is known as a stemness factor in cancer. CD44 splicing variants are involved in cancer stemness. We discovered that SALL4 modulates CD44 alternative splicing through the upregulation of KHDRBS3, a splicing factor for CD44. We cloned the KHDRBS3‐regulated CD44 splicing isoform (CD44v), which lacks exons 8 and 9. CD44v overexpression prevented a reduction in the sphere formation ability by KHDRBS3 knockdown, indicating that CD44v is positively involved in cancer stemness. In addition, CD44v enhanced anoikis resistance under the control of the SALL4 ‐ KHDRBS3 network. Basal‐like breast cancer is an aggressive subtype among breast cancers, and there is no effective therapy so far. Our findings provide molecular targets for basal‐like breast cancer therapy. In the future, this study may contribute to the establishment of drugs targeting cancer stemness

Three-dimensional visualization of thoracodorsal artery perforators using photoacoustic imaging

Introduction: Diagnostic imaging modalities to evaluate the three-dimensional distribution of thoracodorsal artery perforators (TDAPs) are lacking. In this study, TDAPs were visualized and characterized using photoacoustic imaging. Material and methods: In this study, 34 sites in the lateral chest wall of 18 individuals were analyzed. The region extending 5 cm ventral and 5 cm dorsal to the lateral edge of the latissimus dorsi (LD) and 5–15 cm from the posterior axillary fold was scanned using photoacoustic imaging. The largest perforator closest to the edge of the LD was characterized. The location of the stem portion and the orientation of the longest cutaneous branch of the perforator were described. The relationship between the maximal depth of delineation on photoacoustic images and the depth of the deep fascia was assessed. Results: On average, 2.6 perforators (range, 1–5 perforators) were visualized in the region of interest. The distribution of the TDAP stem portion was similar to that in previous studies. Cutaneous branches were preferentially oriented in a medial-caudal direction. The length of delineated cutaneous branches varied (range, 7–78 mm) depending on the thickness of the subcutaneous layer. Vessels under the LD were observed when the subcutaneous layer was thin. Conclusion: Photoacoustic imaging can successfully visualize TDAPs in three dimensions. Visualization of TDAPs varied by the thickness of the subcutaneous layer. A thin deep fascia of the LD might be a cause of deep laser penetration

Biomarkers Predictive of Distant Disease-free Survival Derived from Diffusion-weighted Imaging of Breast Cancer

Purpose: To investigate whether intravoxel incoherent motion (IVIM) and/or non-Gaussian diffusion parameters are associated with distant disease-free survival (DDFS) in patients with invasive breast cancer. Methods: From May 2013 to March 2015, 101 patients (mean age 60.0, range 28-88) with invasive breast cancer were evaluated prospectively. IVIM parameters (flowing blood volume fraction [ɪᴠɪᴍ] and pseudodiffusion coefficient [D*]) and non-Gaussian diffusion parameters (theoretical apparent diffusion coefficient [ADC] at a b value of 0 s/mm² [ADC₀] and kurtosis [K]) were estimated using a diffusion-weighted imaging series of 16 b values up to 2500 s/mm². Shifted ADC values (sADC₂₀₀-₁₅₀₀) and standard ADC values (ADC₀-₈₀₀) were also calculated. The Kaplan-Meier method was used to generate survival analyses for DDFS, which were compared using the log-rank test. Univariable Cox proportional hazards models were used to assess any associations between each parameter and distant metastasis-free survival. Results: The median observation period was 80 months (range, 35-92 months). Among the 101 patients, 12 (11.9%) developed distant metastasis, with a median time to metastasis of 79 months (range, 10-92 months). Kaplan-Meier analysis showed that DDFS was significantly shorter in patients with K > 0.98 than in those with K ≤ 0.98 ( = 0.04). Cox regression analysis showed a marginal statistical association between K and distant metastasis-free survival ( = 0.05). Conclusion: Non-Gaussian diffusion may be associated with prognosis in invasive breast cancer. A higher K may be a marker to help identify patients at an elevated risk of distant metastasis, which could guide subsequent treatment

Delineation of pathogenomic insights of breast cancer in young women

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).The prognosis of breast cancer (BC) in young women (BCYW) aged ≤40 years tends to be poorer than that in older patients due to aggressive phenotypes, late diagnosis, distinct biologic, and poorly understood genomic features of BCYW. Considering the estimated predisposition of only approximately 15% of the BC population to BC-promoting genes, the underlying reasons for an increased occurrence of BCYW, at large, cannot be completely explained based on general risk factors for BC. This underscores the need for the development of next-generation of tissue- and body fluid-based prognostic and predictive biomarkers for BCYW. Here, we identified the genes associated with BCYW with a particular focus on the age, intrinsic BC subtypes, matched normal or normal breast tissues, and BC laterality. In young women with BC, we observed dysregulation of age-associated cancer-relevant gene sets in both cancer and normal breast tissues, sub-sets of which substantially affected the overall survival (OS) or relapse-free survival (RFS) of patients with BC and exhibited statically significant correlations with several gene modules associated with cellular processes such as the stroma, immune responses, mitotic progression, early response, and steroid responses. For example, high expression of COL1A2, COL5A2, COL5A1, NPY1R, and KIAA1644 mRNAs in the BC and normal breast tissues from young women correlated with a substantial reduction in the OS and RFS of BC patients with increased levels of these exemplified genes. Many of the genes upregulated in BCYW were overexpressed or underexpressed in normal breast tissues, which might provide clues regarding the potential involvement of such genes in the development of BC later in life. Many of BCYW-associated gene products were also found in the extracellular microvesicles/exosomes secreted from breast and other cancer cell-types as well as in body fluids such as urine, saliva, breast milk, and plasma, raising the possibility of using such approaches in the development of non-invasive, predictive and prognostic biomarkers. In conclusion, the findings of this study delineated the pathogenomics of BCYW, providing clues for future exploration of the potential predictive and prognostic importance of candidate BCYW molecules and research strategies as well as a rationale to undertake a prospective clinical study to examine some of testable hypotheses presented here. In addition, the results presented here provide a framework to bring out the importance of geographical disparities, to overcome the current bottlenecks in BCYW, and to make the next quantum leap for sporadic BCYW research and treatment.info:eu-repo/semantics/publishedVersio

Serum amyloid alpha 1-2 are not required for liver inflammation in the 4T1 murine breast cancer model

がんに起因して起こる宿主の肝臓の急性期応答と炎症 --血清アミロイドαは乳がんモデルにおける肝臓の炎症の原因ではない--. 京都大学プレスリリース. 2023-02-06.Cancers induce the production of acute phase proteins such as serum amyloid alpha (SAA) in the liver and cause inflammation in various host organs. Despite the well-known coincidence of acute phase response and inflammation, the direct roles of SAA proteins in inflammation in the cancer context remains incompletely characterized, particularly in vivo. Here, we investigate the in vivo significance of SAA proteins in liver inflammation in the 4T1 murine breast cancer model. 4T1 cancers elevate the expression of SAA1 and SAA2, the two major murine acute phase proteins in the liver. The elevation of Saa1-2 correlates with the up-regulation of immune cell-related genes including neutrophil markers. To examine this correlation in detail, we generate mice that lack Saa1-2 and investigate immune-cell phenotypes. RNA-seq experiments reveal that deletion of Saa1-2 does not strongly affect 4T1-induced activation of immune cell-related genes in the liver. Flow cytometry experiments demonstrate the dispensable roles of SAA1-2 in cancer-dependent neutrophil infiltration to the liver. Consistently, 4T1-induced gene expression changes in bone marrow do not require Saa1-2. This study clarifies the negligible contribution of SAA1-2 proteins in liver inflammation in the 4T1 breast cancer model