Checkpoint blockade immunotherapy (CPI) is an effective treatment option for many types of cancers. Irrespective of its wide clinical implications, the overall efficacy remains unpredictable and even ...poor in certain pathologies such as breast cancer. Thus, it is imperative to understand the role of factors affecting its responsiveness. In this review, we provide an overview on the involvement of sociological factors, lifestyles and metabolic disorders in modulating the CPI response in patients from multiple malignancies. Lifestyle habits including exercise, and diet promoted therapeutic responsiveness while alcohol consumption mitigated the CPI effect by decreasing mutational burden and hampering antigen presentation by dendritic cells. Metabolic disorder such as obesity was recognized to enhance the PD-1 expression while diabetes and hypertension were consequences of CPI therapy rather than causes. Among the sociologic factors, sex and race positively influenced the CPI effectiveness on account of increased effector T cell activity and increased PD-1 expression while ageing impaired CPI responsiveness by decreasing functional T cell and increased toxicity. The combined effect of these factors was observed for obesity and gender, in which obese males had the most significant effect of CPI. Therefore these variables should be carefully considered before treating patients with CPI for optimal treatment outcome.
Smoking has a profound impact on tumor immunity, and nicotine, which is the major addictive component of smoke, is known to promote tumor progression despite being a non-carcinogen. In this study, we ...demonstrate that chronic exposure of nicotine plays a critical role in the formation of pre-metastatic niche within the lungs by recruiting pro-tumor N2-neutrophils. This pre-metastatic niche promotes the release of STAT3-activated lipocalin 2 (LCN2), a secretory glycoprotein from the N2-neutrophils, and induces mesenchymal-epithelial transition of tumor cells thereby facilitating colonization and metastatic outgrowth. Elevated levels of serum and urine LCN2 is elevated in early-stage breast cancer patients and cancer-free females with smoking history, suggesting that LCN2 serve as a promising prognostic biomarker for predicting increased risk of metastatic disease in female smoker(s). Moreover, natural compound, salidroside effectively abrogates nicotine-induced neutrophil polarization and consequently reduced lung metastasis of hormone receptor-negative breast cancer cells. Our findings suggest a pro-metastatic role of nicotine-induced N2-neutrophils for cancer cell colonization in the lungs and illuminate the therapeutic use of salidroside to enhance the anti-tumor activity of neutrophils in breast cancer patients.
Bone metastasis is an incurable complication of breast cancer. In advanced stages, patients with estrogen-positive tumors experience a significantly higher incidence of bone metastasis (>87%) ...compared to estrogen-negative patients (<56%). To understand the mechanism of this bone-tropism of ER
tumor, and to identify liquid biopsy biomarkers for patients with high risk of bone metastasis, the secreted extracellular vesicles and cytokines from bone-tropic breast cancer cells are examined in this study. Both exosomal miR-19a and Integrin-Binding Sialoprotein (IBSP) are found to be significantly upregulated and secreted from bone-tropic ER
breast cancer cells, increasing their levels in the circulation of patients. IBSP is found to attract osteoclast cells and create an osteoclast-enriched environment in the bone, assisting the delivery of exosomal miR-19a to osteoclast to induce osteoclastogenesis. Our findings reveal a mechanism by which ER
breast cancer cells create a microenvironment favorable for colonization in the bone. These two secreted factors can also serve as effective biomarkers for ER
breast cancer to predict their risks of bone metastasis. Furthermore, our screening of a natural compound library identifies chlorogenic acid as a potent inhibitor for IBSP-receptor binding to suppress bone metastasis of ER
tumor, suggesting its preventive use for bone recurrence in ER
patients.
Brain metastasis of breast cancer exhibits exceedingly poor prognosis, and both triple negative (TN) and Her2
subtypes have the highest incidence of brain metastasis. Although estrogen blockers are ...considered to be ineffective for their treatment, recent evidence indicates that estrogen blockade using tamoxifen showed certain efficacy. However, how estrogen affects brain metastasis of triple negative breast cancer (TNBC) remains elusive.
To examine the effect of estrogen on brain metastasis progression, nude mice were implanted with brain metastatic cells and treated with either estrogen supplement, tamoxifen, or ovariectomy for estrogen depletion. For clinical validation study, brain metastasis specimens from pre- and post-menopause breast cancer patients were examined for microglia polarization by immunohistochemistry. To examine the estrogen-induced M2 microglia polarization, microglia cells were treated with estrogen, and the M1/M2 microglia polarization was detected by qRT-PCR and FACS. The estrogen receptor-deficient brain metastatic cells, SkBrM and 231BrM, were treated with conditioned medium (CM) derived from microglia that were treated with estrogen in the presence or absence of tamoxifen. The effect of microglia-derived CM on tumor cells was examined by colony formation assay and sphere forming ability.
We found that M2 microglia were abundantly infiltrated in brain metastasis of pre-menopausal breast cancer patients. A similar observation was made in vivo, when we treated mice systemically with estrogen. Blocking of estrogen signaling either by tamoxifen treatment or surgical resection of mice ovaries suppressed M2 microglial polarization and decreased the secretion of C-C motif chemokine ligand 5, resulting in suppression of brain metastasis. The estrogen modulation also suppressed stemness in TNBC cells in vitro. Importantly, estrogen enhanced the expression of signal regulatory protein α on microglia and restricted their phagocytic ability.
Our results indicate that estrogen promotes brain metastasis by skewing polarity of M2 microglia and inhibiting their phagocytic ability, while tamoxifen suppresses brain metastasis by blocking the M2 polarization of microglia and increasing their anti-tumor phagocytic ability. Our results also highlight a potential therapeutic utility of tamoxifen for treating brain metastasis of hormone receptor-deficient breast cancer.
Ductal carcinoma in situ (DCIS) of breast is the noninvasive lesion that has propensity to progress to the malignant form. At present, it is still unknown which lesions can potentially progress to ...invasive forms. In this study, we aimed to identify key lncRNAs involved in DCIS growth.
We employ disease-related lncProfiler array to identify IPW in specimens of DCIS and matching control samples and validate the observations in three DCIS-non-tumorigenic cell lines. Further, we examine the mechanism of IPW action and the downstream signaling in in vitro and in vivo assays. Importantly, we screened a library containing 390 natural compounds to identify candidate compound selectively inhibiting IPW low DCIS cells.
We identified lncRNA IPW as a novel tumor suppressor critical for inhibiting DCIS growth. Ectopic expression of IPW in DCIS cells strongly inhibited cell proliferation, colony formation and cell cycle progression while silencing IPW in primary breast cells promoted their growth. Additionally, orthotropic implantation of cells with ectopic expression of IPW exhibited decreased tumor growth in vivo. Mechanistically, IPW epigenetically enhanced miR-29c expression by promoting H3K4me3 enrichment in its promoter region. Furthermore, we identified that miR-29c negatively regulated a stemness promoting gene, ID2, and diminished self-renewal ability of DCIS cells. Importantly, we screened a library containing 390 natural compounds and identified toyocamycin as a compound that selectively inhibited the growth of DCIS with low expression of IPW, while it did not affect DCIS with high IPW expression. Toyocamycin also suppressed genes associated with self-renewal ability and inhibited DCIS growth in vivo.
Our findings revealed a critical role of the IPW-miR-29c-ID2 axis in DCIS formation and suggested potential clinical use of toyocamycin for the treatment of DCIS.
Astrocytoma is recognized as the most common neoplasm of the brain with aggressive progression. The therapeutic regime for glioblastoma, the most aggressive astrocytoma, often consists of aggressive ...chemo and radiotherapy. The present holistic approaches, however, have failed to influence the quality life of patients. Therefore, it is necessary to understand the underlying mechanisms of its progression for updated therapeutic evaluation. Human cytomegalovirus (HCMV) is reported to be associated with glioblastoma progression. The hypothesis still remains controversial due to the lack of concrete evidences. Here, we report the profile of miRNAs encoded by human host and the cytomegalovirus (CMV) involved in modulation of CMV infection in surgically resected human astrocytoma tissue samples of various malignancy grades (
n
= 24). Total RNA from the control brain and tumor tissues was extracted by TriZol reagent. The expression levels of the mature form of miRNA were detected by real-time PCR. Primarily, we found the upregulation of miR-210-3p, miR-155-5p, miR-UL-112-3p, miR-183-5p, and miR-223-5p in high-grade astrocytic tumors as compared with low-grade tumor tissues. miR-214-3p is significantly expressed in control brain tissues and its expression decreased with astrocytoma grade progression. This miRNA was reported to be associated with antiviral proprieties. Among CMV-encoded miRNA, miR-UL-112-3p was significantly upregulated in glioblastoma tissue samples and may be involved in providing immune escape to the virus as well as involved in modulating the immune microenvironment of glioblastoma. Taken together, we conclude the possible involvement of miRNAs in modulating the CMV dependent astrocytoma progression.
Astrocytomas are the most common brain tumors with poor survival in malignant forms. Signal regulatory protein alpha (SIRP alpha) is a transmembrane protein expressed on immune cells and macrophages ...and is reported to modulate tumor cell phagocytosis. In the present study, we investigated the involvement of miR-520d-5p and miR-520d-3p in regulation of SIRP alpha expression. Here, we report mRNA and protein expression profile of SIRP alpha in 39 surgically resected human astrocytoma tissue samples and 14 control brain tissue samples. Transcript expression pattern was studied by real-time PCR while Western blotting and immunohistochemistry were used to evaluate protein expression. Expression profile of miR-520d-5p and miR-520d-3p was studied by real-time PCR. Computational prediction was employed to analyze the binding of miR-520d-5p and miR-520d-3p for SIRP alpha mRNA. It is evident from preliminary investigation that SIRP alpha transcripts are expressed in control brain tissues, increased in low-grade (grade II) tumor tissues, and decreased with further grade progression (
P
< 0.05). SIRP alpha protein was moderately expressed in control brain tissues but under-expressed in low- and high-grade tissue samples (
P
< 0.05). Immunohistochemistry results further confirmed Western blot outcomes. Computational prediction supplemented with 3′ and 5′UTR targeting analysis and correlation studies reveals that hsa-miR-520d-5p (
P
= 0.028,
R
2
= 0.94) (95 % CI 0.15 to 0.99) and hsa-miR-520d-3p (
P
= 0.027,
R
2
= 0.94) (95% CI 0.17 to 0.99) may be the putative microRNAs involved in regulation of SIRP alpha protein expression. Real-time PCR expression profile depicts that mature form of both miRNAs is significantly overexpressed in low-grade (GII) tumor tissue samples compared to control and high-grade (GIII and GIV) tissue samples. MiR-520d-5p and miR-520d-3p were found with expression pattern similar to SIRP alpha transcripts. We show that SIRP alpha protein is under-expressed in low and high grades of astrocytoma patients’ tissue samples. Control brain tissues were found to be positive with SIRP alpha protein expression. Real-time PCR expression analysis confirms that miR-520d-5p and miR-520d-3p expression levels were significantly correlated with SIRP alpha transcripts in control, low-grade, and high-grade tissue samples. Computational prediction further evidenced for binding sites of these miRNAs on 3′ and 5′UTR of SIRP alpha transcripts. Taken together, we predict that miR-520d-5p and miR-520d-3p may be having role in the regulation of under-expressed SIRP alpha protein expression.
Astrocytoma is the most frequent malignancies of the brain. Despite present clinical advancements, median survival time in malignant forms remains poor. Downstream of kinase protein 2 (Dok2) is ...adaptor protein known to modulate the effect of tyrosine kinase. Previously, Dok2 is shown to be marker of poor prognosis in colorectal and gastric cancer, and reduced levels of Dok2 were reported in lung adenocarcinoma and gastric cancer. The aim of the present study was to evaluate prognostic significance of pDok2 expression in surgically resected astrocytoma tissue samples. In the present study, 47 numbers of tissue samples were collected from patients who underwent surgery for astrocytoma. Temporal lobe epilepsy tissues were used as control. Real-time PCR was used to study transcript expression while protein expression was studied by western blotting and immunohistochemistry. The pDok2 expression was categorized as pDok2 positive and pDok2 negative on the basis of intensity of protein expression. This observation was confirmed by two independent pathologists. Control and few GII tissues were used as reference on account for low expression of pDok2 protein. Basic information of patients as anatomic origin of tumor and follow-up details were retrieved from hospital registry. Kaplan-Meier test was used to analyze the association of pDok2 expression and survival outcome in clinical cases. Real-time PCR signifies pDok2 is overexpressed in high-grade (GIII + GIV) tissue samples compared with low-grade (GII) and control brain tissue samples (
p
< 0.005). Western blotting and immunohistochemistry analysis signifies overexpression of pDok2 protein expression in tumor tissue samples as compared with control brain tissues. Clinico-pathological analysis reveals 83% of high-grade astrocytoma (GIII + GIV) and 30% of low-grade (GII) tissue samples which were detected with pDok2 expression. Tumor location was found to be predominant at the frontal and temporal lobes. Survival studies underline prognostic importance of pDok2 protein. Median survival of 20 months was reported with patients with positive pDok2 expression (95% CI 0.083 to 0.49). Taken together, pDok2 protein overexpression is associated with poor prognosis in astrocytoma clinical cases and appears to be an attractive target for therapeutic intervention. Noticeable anatomic origin at the frontal and temporal lobe suggests site-specific role of developmental factors in tumor occurrence.
Astrocytoma constitutes the most noted malignancies of the central nervous system with worse clinical outcomes in grade IV astrocytoma or glioblastoma multiforme. Owing to poor clinical outcomes with ...existing therapeutic regime, there is a need to revisit the initial course of treatment. Statistical information of clinicopathological parameters could be used to understand the spread of disease and, in turn, to formulate updated treatment management. In the present study, we have seen anatomic distribution of astrocytoma subtypes in a group of 479 patients and correlated it with survival outcomes. Anatomic location was confirmed by MRI (magnetic resonance imaging) images. A registry of patients was maintained with clinicopathological details as tumor type, location, age/sex, and survival after surgery. We have observed overall survival particulars in patients diagnosed with astrocytoma. Our findings highlight that in total cases, tumor location was anatomically dominated by frontal and temporal lobes. Survival analysis in high-grade (grade III,
p
= 0.03; grade IV,
p
= 0.01) astrocytic tumors confirms poor outcomes with temporal, parietal, and occipital location as compared to frontal lobe. Overall survival study demonstrates glioblastoma multiforme (GBM) was associated with worse prognosis as compared to astrocytoma subtypes (
p
< 0.0001). In high-grade astrocytomas, anaplastic astrocytoma was found with 34 months of median survival age while 14 months in the case of patients with glioblastoma multiforme. In conclusion, we report dismal prognosis in parietal, temporal, and occipital lobes in grade II, grade III, and grade IV astrocytoma patients. Among astrocytoma subtypes, patients with glioblastoma multiforme were associated with worse survival outcomes. We uniquely feature the survival of astrocytoma patients for the first time and observe GBM patients have slightly longer survival.
Brainstem glioma: Clinical significance and prognostic evaluation Deshpande, Ravindra Pramod; Chandrasekhar, Y.B.V.K.; Babu, Deepak ...
Interdisciplinary neurosurgery : Advanced techniques and case management,
June 2019, 2019-06-00, 2019-06-01, Letnik:
16
Journal Article
Recenzirano
Odprti dostop
In the present study, we have determined the prognostic value and observed the clinicopathological features of brainstem glioma. Overall, we found more number of male patients with brainstem glioma ...(male:female ratio: 1:6). All patients were subjected to surgery followed by chemotherapy. The tumor was mainly located at brainstem and thalamus. We have recorded the symptoms associated with onset of lesions and predominated by headache, vomiting and limb weakness. We observed the overall survival pattern in brain stem glioma cases and further among low and high grade subgroups. Patients with high grade brainstem glioma were recorded with the median survival of 15 months. There was a statistically significant difference in the survival pattern of low grade vs high grade group (p = 0.015, hazard ratio: 0.29, 95% CI of ratio: 0.058 to 0.71) Taken together, the clinical presentation provides valuable information to enhance the therapeutic measures for the brainstem glioma cases.
•Gliomas with brain stem location are known to occur rarely and have complex pathology.•We present the clinical features and survival outcome of brain stem glioma cases.•All patients were subjected to surgical resection followed by chemotherapy.•Patients with high grade brainstem glioma were recorded with the median survival of 15 months.
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