Hormones and Cancer

Tumor-infiltrating immune cells and fibroblasts are significant components of the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC), and they participate in tumor progression as closely as tumor cells. However, the relationship between the features of the TME and patient outcomes and the interactions among TME components are still unclear. In this study, we evaluated the PDAC TME in terms of the quantity and location of cluster of differentiation (CD)4+ T cells, CD8+ T cells, macrophages, stromal maturity, and tumor-stroma ratio (TSR), as evaluated by immunohistochemical staining of serial whole-tissue sections from 116 patients with PDAC. The density of T cells and macrophages (mainly activated macrophages) was significantly higher at the invasive margins (IMs) than at the tumor center (TC). CD4+ T cells were significantly association with all the other tumor-associated immune cells (TAIs) including CD8, CD68 and CD206 positive cells. Tumors of the non-mature (intermediate and immature) stroma type harbored significantly more CD8+ T cells at the IMs and more CD68+ macrophages at the IMs and the TC. The density of CD4+, CD8+, and CD206+ cells at the TC; CD206+ cells at the IMs; and tumor-node-metastasis (TNM) staging were independent risk factors for patient outcomes, and the c-index of the risk nomogram for predicting the survival probability based on the TME features and TNM staging was 0.772 (95% confidence interval: 0.713–0.832). PDAC harbored a significantly immunosuppressive TME, of which the IMs were the hot zones for TAIs, while cells at the TC were more predictive of prognosis. Our results indicated that the model based on the features of the TME and TNM staging could predict patient outcomes.

There is a great need to reduce the toxicity of chemotherapy used in the management of pancreatic ductal adenocarcinoma (PDAC). Here we explore if regional pressurized delivery of oxaliplatin can minimize peripheral neuropathy in mice. We used an orthotopic PDAC mouse model and delivered a single dose of oxaliplatin through the portal vein using a pressure-enabled system (pancreatic retrograde venous infusion, PRVI). We analyzed the effects of PRVI on tumor burden and peripheral neuropathy using histopathological and functional assays. Tumor weights in mice treated with 2 mg/kg oxaliplatin using PRVI were significantly lower than in mice treated with the same dose systemically. This resulted in reduced peripheral neuropathy signatures in PRVI mice compared to the 20 mg/kg systemic dose required to achieve similar tumor control. Regional delivery of highly cytotoxic agents using PRVI can reduce the therapeutic dose of these drugs, thereby lowering toxic side effects.

Membrane overexpression of ErbB-2 (MErbB-2), a member of the ErbB family of receptor tyrosine kinases, occurs in 15–20% of breast cancers (BC) and constitutes a therapeutic target in this BC subtype (ErbB-2-positive). Although MErbB-2-targeted therapies have significantly improved patients’ clinical outcome, resistance to available drugs is still a major issue in the clinic. Lack of accurate biomarkers for predicting responses to anti-ErbB-2 drugs at the time of diagnosis is also an important unresolved issue. Hence, a better understanding of the ErbB-2 signaling pathway constitutes a critical task in the battle against BC. In its canonical mechanism of action, MErbB-2 activates downstream signaling pathways, which transduce its proliferative effects in BC. The dogma of ErbB-2 mechanism of action has been challenged by the demonstration that MErbB-2 migrates to the nucleus, where it acts as a transcriptional regulator. Accumulating findings demonstrate that nuclear ErbB-2 (NErbB-2) is involved in BC growth and metastasis. Emerging evidence also reveal a role of NErbB-2 in the response to available anti-MErbB-2 agents. Here, we will review NErbB-2 function in BC and will particularly discuss the role of NErbB-2 as a novel target for therapy in ErbB-2-positive BC.

Bladder cancer (BLCA) is a prevalent urinary system malignancy. Understanding the interplay of immunological and metabolic genes in BLCA is crucial for prognosis and treatment. Immune/metabolism genes were extracted, their expression profiles analyzed. NMF clustering found prognostic genes. Immunocyte infiltration and tumor microenvironment were examined. Risk prognostic signature using Cox/LASSO methods was developed. Immunological Microenvironment and functional enrichment analysis explored. Immunotherapy response and somatic mutations evaluated. RT-qPCR validated gene expression. We investigated these genes in 614 BLCA samples, identifying relevant prognostic genes. We developed a predictive feature and signature comprising 7 genes (POLE2, AHNAK, SHMT2, NR2F1, TFRC, OAS1, CHKB). This immune and metabolism-related gene (IMRG) signature showed superior predictive performance across multiple datasets and was independent of clinical indicators. Immunotherapy response and immune cell infiltration correlated with the risk score. Functional enrichment analysis revealed distinct biological pathways between low- and high-risk groups. The signature demonstrated higher prediction accuracy than other signatures. qRT-PCR confirmed differential gene expression and immunotherapy response. The model in our work is a novel assessment tool to measure immunotherapy’s effectiveness and anticipate BLCA patients’ prognosis, offering new avenues for immunological biomarkers and targeted treatments.

Elevated mammographic density is a breast cancer risk factor, which has a suggestive, but unproven, relationship with increased exposure to sex steroid hormones. We examined associations of serum estrogens and estrogen metabolites with area and novel volume mammographic density measures among 187 women, ages 40–65, undergoing diagnostic breast biopsies at an academic facility in Vermont. Serum parent estrogens, estrone and estradiol, and their 2-, 4-, and 16-hydroxylated metabolites were measured using liquid chromatography-tandem mass spectrometry. Area mammographic density was measured in the breast contralateral to the biopsy using thresholding software; volume mammographic density was quantified using a density phantom. Linear regression was used to estimate associations of estrogens with mammographic densities, adjusted for age and body mass index, and stratified by menopausal status and menstrual cycle phase. Weak, positive associations between estrogens, estrogen metabolites, and mammographic density were observed, primarily among postmenopausal women. Among premenopausal luteal phase women, the 16-pathway metabolite estriol was associated with percent area (p = 0.04) and volume (p = 0.05) mammographic densities and absolute area (p = 0.02) and volume (p = 0.05) densities. Among postmenopausal women, levels of total estrogens, the sum of parent estrogens, and 2-, 4- and 16-hydroxylation pathway metabolites were positively associated with area density measures (percent: p = 0.03, p = 0.04, p = 0.01, p = 0.02, p = 0.07; absolute: p = 0.02, p = 0.02, p = 0.01, p = 0.02, p = 0.03, respectively) but not volume density measures. Our data suggest that serum estrogen profiles are weak determinants of mammographic density and that analysis of different density metrics may provide complementary information about relationships of estrogen exposure to breast tissue composition.

Resistance to the latest advanced prostate cancer therapies, including abiraterone and enzalutamide, is associated with increased expression of constitutively active androgen receptor splice variants (AR-Vs). The exact mechanism by which these therapies result in AR-Vs is unknown, but may include genomic rearrangement of the androgen receptor gene as well as alternative splicing of the AR pre-messenger RNA (mRNA). An additional complication that hinders further development of effective AR strategies is that the mechanisms by which the directed therapies are bypassed may vary. Finally, the question must be addressed as to whether the androgen receptor remains to be the driver of most castration resistant disease or whether truly AR-independent tumors arise after successful androgen ablation therapy. In this review, we will examine androgen receptor splice variants as an alternative mechanism by which prostate cancer becomes resistant to androgen receptor-directed therapy.