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We conducted a comparative study of the mammary gland microbiota in female Wistar rats and the microbiota associated with breast cancer (BC) induced by the administration of N-methyl-N-nitrosourea, after surgical treatment, photodynamic therapy (PDT), and chemotherapy (CT). Selective nutrient media and a smear-fingerprint technique were used to study the microbiota. Staphylococcus , Streptococcus , and Lactobacillus were found in the mammary glands of intact rats. The mean number of Staphylococcus CFU increased statistically significantly in all groups of rats with induced BC, compared to intact animals: by 8 times in the BC without treatment group, by 15% in BC+surgery, by 10 times in BC+PDT, by 4 times in BC+PDT+CT, and by 13 times in BC+CT. The number of Streptococcus CFU also increased in all experimental groups: by 15.5 times in the BC without treatment group, by 4 times in BC+surgery, by 2.6 times in BC+PDT, by 4.5 times in BC+PDT+CT, and by 3.5 times in BC+CT. The number of Lactobacillus CFU significantly increased only in the BC+PDT group (by 2.5 times). The development of the microbiota in the tumor allows evaluating the impact of various types of therapy on the growth of opportunistic microorganisms. The results suggest that doxorubicin combined with PDT has the most potent effect on changes to the tumor microbiota.

A histological study of structural changes in the thymus of female Wistar rats with chemically induced breast cancer (BC) after photodynamic therapy (PDT) and a combination of PDT and surgical treatment was conducted. After PDT, the thymus showed restoration of the cortical and medullary substance areas, as well as glandular tissue, to the values of the intact control in comparison with the pathological control (BC without treatment). PDT influences both positive and negative selection processes and the activity of T-lymphocyte differentiation processes (the number of epithelial cells and macrophages increases, the number of cells with pyknotic nuclei in the cortical and medullary substance decreases). In the cortico-medullary zone of the thymus, the number of small and medium lymphocytes increases, which may indicate an increase in lymphocyte migration from the thymus. After PDT and subsequent resection of a BC, structural changes in the thymus may indicate a decrease in its lymphopoietic function, activity of both positive and negative T-cell selection processes, as well as a decrease in the activity of T-lymphocyte differentiation processes and their migration from the thymus.

A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4). However, the determinants of response to anti-CTLA-4 mAb treatment remain incompletely understood. In murine models, anti-CTLA-4 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions, including local ionizing radiation (IR) therapy. We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor-infiltrating CD8+ T lymphocytes (TILs) following treatment with the anti-CTLA-4 mAb 9H10. Alone, 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo. In contrast, the combination of 9H10 and IR restored MHC class I-dependent arrest. After implantation, the carcinoma cells had reduced expression of retinoic acid early inducible-1 (RAE-1), a ligand for natural killer cell group 2D (NKG2D) receptor. We found that RAE-1 expression was induced by IR in vivo and that anti-NKG2D mAb blocked the TIL arrest induced by IR/9H10 combination therapy. These results demonstrate that anti-CTLA-4 mAb therapy induces motility of TIL and that NKG2D ligation offsets this effect to enhance TILs arrest and antitumor activity.

Background: Re-irradiation is an essential treatment option for recurrent tumours but is limited by normal tissue tolerance. Hyperthermia can enhance radiation efficacy by impairing DNA repair and improving tumor oxygenation; however, limited preclinical data are evaluating its combination with re-irradiation in recurrent tumor settings and normal skin. Objective: The study aims to determine optimal priming doses for skin and tumor response and evaluate the radiosensitising effect of hyperthermia when combined with re-irradiation in preclinical models. Methods: The right rear foot of non-tumor-bearing CDF1 mice or a C3H mammary carcinoma implanted in the foot were treated with a single radiation dose or reirradiation + hyperthermia (42.5°C, 1-h). Initial experiments identified a priming dose of 30 Gy that induced moderate but reversible acute skin toxicity and a tumor dose of 40 Gy that resulted in full regression with regrowth in 30-35 days from treatment. Reirradiation dose-response studies were conducted to determine the МОР; (skin) and TCDs, (tumor) with and without hyperthermia. Thermal Enhancement Ratios (TER) and Therapeutic Gain Factor (TGF) were calculated. Results: The MDDs, for reirradiation-induced skin damage was 25 Gy, reduced to 18 Gy with hyperthermia (TER = 1.4). In tumours, the TCDs, decreased from 49 Gy (reirradiation alone) to 29 Gy with hyperthermia (TER = 1.7). ATGF of 1.2 was observed, indicating selective enhancement of tumor response relative to skin toxicity. Conclusion: Hyperthermia enhances the therapeutic effect of reirradiation by improving tumor control at lower doses, supporting its potential in recurrent cancer treatment strategies.

PurposeThe present study aimed to investigate the molecular mechanisms underlying the anticancer properties of ginger extract (GE) in mice bearing solid Ehrlich carcinoma (SEC) and to evaluate the use of GE in combination with doxorubicin (DOX) as a complementary therapy against SEC.MethodsSEC was induced in 60 female mice. Mice were divided into four equal groups: SEC, GE, DOX and GE + DOX. GE (100 mg/kg orally day after day) and DOX (4 mg/kg i.p. for 4 cycles every 5 days) were given to mice starting on day 12 of inoculation. On the 28th day, blood samples were collected, mice were scarified, tumor volume was measured, and tumor tissues were excised.ResultsThe anti-cancer effect of GE was mediated by activation of adenosine monophosphate protein kinase (AMPK) and down-regulation of cyclin D1 gene expression. GE also showed pro-apoptotic properties as evidenced by elevation of the P53 and suppression of nuclear factor-kappa B (NF-κB) content in tumor tissue. Co-administration of GE alongside DOX markedly increased survival rate, decreased tumor volume, and increased the level of phosphorylated AMPK (PAMPK) and improved related pathways compared to DOX group. In addition, the histopathological results demonstrated enhanced apoptosis and absence of multinucleated cells in tumor tissue of GE + DOX group.ConclusionAMPK pathway and cyclin D1 gene expression could be a molecular therapeutic target for the anticancer effect of GE in mice bearing SEC. Combining GE and DOX revealed a greater efficacy as anticancer therapeutic regimen.

This pre-clinical study was designed to demonstrate how vascular disrupting agents (VDAs) should be administered, either alone or when combined with radiation in clinically relevant fractionated radiation schedules, for the optimal anti-tumor effect. CDF1 mice, implanted in the right rear foot with a 200 mm3 murine C3H mammary carcinoma, were injected with various doses of the most potent VDA drug, combretastatin A-1 phosphate (CA1P), under different schedules. Tumors were also locally irradiated with single-dose, or stereotactic (3 × 5–20 Gy) or conventional (30 × 2 Gy) fractionation schedules. Tumor growth and control were the endpoints used. Untreated tumors had a tumor growth time (TGT5; time to grow to 5 times the original treatment volume) of around 6 days. This increased with increasing drug doses (5–100 mg/kg). However, with single-drug treatments, the maximum TGT5 was only 10 days, yet this increased to 19 days when injecting the drug on a weekly basis or as three treatments in one week. CA1P enhanced radiation response regardless of the schedule or interval between the VDA and radiation. There was a dose-dependent increase in radiation response when the combined with a single, stereotactic, or conventional fractionated irradiation, but these enhancements plateaued at around a drug dose of 25 mg/kg. This pre-clinical study demonstrated how VDAs should be combined with clinically applicable fractionated radiation schedules for the optimal anti-tumor effect, thus suggesting the necessary pre-clinical testing required to ultimately establish VDAs in clinical practice.

Cancer immune-therapy is an interesting avenue of studying the effects of deviating immune system responses to achieve the desired result. Lactobacilli are inhabitants of the GI tract which have shown beneficial health effects on various ailments including malignancies. Their mechanisms of action comprise a very intense area of research. In this study we evaluated the immunomodulatory effects of Lactobacillus acidophilus in in vivo model of breast cancer. Lactobacillus acidophilus ( L.a ) was isolated from traditional home-made yogurt and also from neonatal stool by aerobic overnight culture at 37°C in MRS broth. Delayed Type Hypersensitivity (DTH) assay was performed to find the best immunostimulant dose. 4T1 tumour bearing mice were treated with 2 × 10 8  cfu of isolated L. acidophilus and 20 mg/kg Cyclophosphamide for 15 consecutive days. Tumour volume was measured using a digital vernier calliper. Lymphocyte proliferation was done using MTT proliferation assay. Production of IFNγ, IL-4 and TGF-β from cultured Splenocytes was assessed in the presence of purified tumour antigen. According to results administration of L.a induced a significant decrease in tumour growth pattern (P value = 0.00). Significant alterations in splenocyte production of IFN-γ, IL-4 and TGf-β (P values < 0.05) and also lymphocyte proliferation in L.a treated animals was evident (P value < 0.05). This study indicated that oral administration of L.a is able to alter the cytokine production in tumour bearing mice into a Th1 protective pattern, favourable to anti tumour immunity. Reduced tumour growth rate and increased lymphocyte proliferation are also thus supportive. Further studies are required to elucidate the exact mechanism by which local actions of probiotics affect the systemic immune responses against transformed cells.

Purpose: The present study aims to investigate the antitumor effect and possible mechanisms of chlorin e6 (Ce6)-mediated sono-photodynamic therapy (Ce6-SPDT) on murine 4T1 mammary cancer cells in vitro. Materials: Cellular uptake and intracellular distribution of Ce6 in 4T1 cells were detected by flow cytometry and confocal microscope. Cells after loading with 1 μg/mL Ce6 were exposed to ultrasound at 1.0 MHz for up to 1 minute with an intensity of 0.36 W/cm2 and laser light with total radiation dose of 1.2 J/cm2. Cell viability and clonogenicity were determined by MTT assay and colony formation assay. Apoptosis was analyzed by DAPI staining, Western blots were used to detect the activity of Caspase-3. DNA damage, mitochondrial membrane potential (MMP), and intracellular reactive oxygen species (ROS) of 4T1 cells were also evaluated by flow cytometry. FD500 was employed to detect changes of membrane permeability after ultrasound. Results: Ce6 rapidly entered 4T1 cells within 4 hours after it has been added and displayed a mitochondria-localization pattern. Compared with sonodynamic therapy (SDT) and photodynamic therapy (PDT) alone, the combined SPDT treatment further enhanced cell viability loss, DNA damage, and clonogenicity inhibition. DAPI staining and western blots analysis reflected that cells with apoptotic morphological characteristics and the activity of Caspase-3 were apparently increased in the combined group. Besides, SPDT caused obvious MMP loss and intracellular ROS generation at early 1 hour post treatment. Interestingly, the SPDT induced cell viability loss and cell apoptosis was greatly inhibited by pre-treatment with ROS scavenger N-acetylcysteine and Caspase inhibitor z-VAD-fmk. FD500 detection showed that ultrasound enhanced cell membrane permeability, implying much higher uptake of Ce6 might be involved in PDT therapy by pre-ultrasound treatment. Conclusions: The findings demonstrated that Ce6-mediated SPDT enhanced the antitumor efficacy on 4T1 cells compared with SDT and PDT alone, a Caspase-dependent apoptosis and loss of MMP, generation of ROS may be involved.

Radiotherapy (RT) is a standard treatment for breast cancer; however, it can induce unfavorable alterations in the tumor microenvironment (TME), including inflammatory responses, fibrosis, and immune dysregulation, which may compromise therapeutic efficacy and contribute to suboptimal treatment outcomes. This study aimed to investigate whether Vactosertib, a TGF-β receptor I inhibitor, could modulate RT-induced TME changes and improve treatment outcomes. A breast tumor-bearing mouse model was established and treated with RT alone or in combination with Vactosertib. Mice received fractionated irradiation (4 Gy/day for 3 days) and oral administration of Vactosertib (2.5 mg/kg for 2 weeks). Tumor progression, gene expression, cytokine profiles, immune cell infiltration, and fibrosis were analyzed using microarray analysis, quantitative RT-PCR, ELISA, and histological assessments. RT alone reduced tumor volume but induced transcriptional and cytokine changes associated with inflammation and fibrosis within tumor tissues. In contrast, combination treatment with Vactosertib significantly enhanced tumor suppression compared with RT alone. This was accompanied by reduced expression of pro-inflammatory cytokines, decreased collagen deposition, and increased infiltration of CD8+ T cells, indicating a shift toward a more favorable anti-tumor immune microenvironment. These findings suggest that Vactosertib may enhance the therapeutic efficacy of RT by modulating radiation-induced inflammatory and fibrotic changes in the TME, supporting its potential as a rational combination strategy to improve RT outcomes in breast cancer.

Breast cancer is the most prevalent malignancy in women, which remains untreatable once metastatic. The treatment of advanced breast cancer is restricted due to chemotherapy resistance. We previously investigated anti-cancer potential of a tumor selective oncolytic adenovirus along with cisplatin in three lung cancer cells; A549, H292, and H661, and found it very efficient. To our surprise, this virotherapy showed remarkable cytotoxicity to chemo-resistant cancer cells. Here, we extended our investigation by using two breast cancer cells and their resistant sublines to further validate CRAd’s anti-resistance properties. Results of in vitro and in vivo analyses recapitulated the similar anti-tumor potential of CRAd. Based on the molecular analysis through qPCR and western blotting, we suggest upregulation of coxsackievirus-adenovirus receptor (CAR) as a selective vulnerability of chemotherapy-resistant tumors. CAR knockdown and overexpression experiments established its important involvement in the success of CRAd-induced tumor inhibition. Additionally, through transwell migration assay we demonstrate that CRAd might have anti-metastatic properties. Mechanistic analysis show that CRAd pre-treatment could reverse epithelial to mesenchymal transition in breast cancer cells, which needs further verification. These insights may prove to be a timely opportunity for the application of CRAd in recurrent drug-resistant cancers.