Targeting tumor microenvironment to curb chemoresistance via novel drug delivery strategies

Introduction: Tumor is a heterogeneous mass of malignant cells co-existing with non-malignant cells. This co-existence evolves from the initial developmental stages of the tumor and is one of the hallmarks of cancer providing a protumorigenic niche known as tumor microenvironment (TME). Proliferation, invasiveness, metastatic potential and maintenance of stemness through cross-talk between tumors and its stroma forms the basis of TME.

Areas covered: The article highlights the developmental phases of a tumor from dysplasia to the formation of clinically detectable tumors. The authors discuss the mechanistic stages involved in the formation of TME and its contribution in tumor outgrowth and chemoresistance. The authors have reviewed various approaches for targeting TME and its hallmarks along with their advantages and pitfalls. The authors also highlight cancer stem cells (CSCs) that are resistant to chemotherapeutics and thus a primary reason for tumor recurrence thereby, posing a challenge for the oncologists.

Expert opinion: Recent understanding of the cellular and molecular mechanisms involved in acquired chemoresistance has enabled scientists to target the tumor niche and TME and modulate and/or disrupt this communication leading to the transformation from a tumor-supportive niche environment to a tumor-non-supporting environment and give synergistic results towards an effective management of cancer.     

Aberrant Expression of Markers of Cancer Stem Cells in Gastric Adenocarcinoma and their Relationship to Vasculogenic Mimicry

Background: Gastric cancer is the second leading cause of cancer-related death in Asia, and the majoritytype is gastric adenocarcinoma (GAC). Most GAC patients die of recurrence and metastasis. Cancer stem cells(CSCs) have been thought to be responsible for the initiation, development, metastasis, and ultimately recurrenceof cancer. In this study, we aimed to investigate expression and clinical significance of CSCs markers, CD133 andLgr5, and vasculogenic mimicry (VM) in primary GAC. Materials and Methods: Specimens from 261 Chinesepatients with follow-up were analyzed for CD133, Lgr5 protein expression and VM by immunohistochemicaland histochemical staining. The Pearson Chi’s square test was used to assess the associations among the positivestaining of these markers and clinicopathological characteristics. Postoperative overall survival time was werestudied by univariate and multivariate analyses. Results: In GAC tissues, positive rates of 49.0%, 38.7%, and26.8% were obtained for CD133, Lgr5, and VM, respectively. The mean score of microvessel density (MVD)was 21.7±11.1 in GAC tissues. There was a significantly difference between the positive and negative groups.There was a positive relationship between the VM, the expression of CD133 and Lgr5, and the score of MVDand the grades of tumor, lymph node metastasis, TNM stages (all p<0.05). The overall mean survival time ofthe patients with CD133, Lgr5, VM, and MVD (≥22) positive expression was lower than that of patients withnegative expression. The score of MVD, positive expression of CD133 and VM were independent prognosticfactors of GAC (p<0.05). Conclusions: VM, and expression of CD133, Lgr5, and the score of MVD are relatedto grades of tumor, lymph node metastasis, TNM stages, and overall mean survival time. It is suggested thatCSCs and VM could play an important role in the evolution of GAC.     

Correlation of Skp2 overexpression to prognosis of patients with nasopharyngeal carcinoma from South China

S-phase kinase-associated protein 2 (Skp2), which plays a role in cell cycle regulation, is commonly overexpressed in a variety of human cancers and associated with poor prognosis. However, its role in nasopharyngeal carcinoma (NPC) is not well understood. In this study, we examined the clinical significance of Skp2, with a particular emphasis on overall survival (OS) and disease-free survival (DFS), in NPC cases in South China, where NPC is an epidemic. Additionally, we explored the function of Skp2 in mai...     

Heterogeneity of hepatocellular carcinoma contributes to cancer progression

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease displaying differences in angiogenesis, extracellular matrix proteins, the immune microenvironment and tumor cell populations. Additionally, genetic variations and epigenetic changes of HCC cells could lead to aberrant signaling pathways, induce cancer stem cells and enhance tumor progression. Thus, the heterogeneity in HCC contributes to disease progression and a better understanding of its heterogeneity will greatly aid in the development of strategies for the HCC treatment.     

Angiomotin基因沉默增强乳腺癌干细胞特性及其机制探讨

目的:研究Angiomotin(Amot)基因沉默后对乳腺癌干细胞特性的影响,初步评估Amot在乳腺癌中异常表达的分子机制。方法:运用免疫组化、Western blot及RT-qPCR技术在乳腺癌组织及乳腺癌细胞株中验证Amot的表达,进而运用RNA干扰技术特异性地阻断Amot在乳腺癌高表达细胞株MCF-7中的表达,以期了解Amot沉默后对乳腺癌干细胞特性的影响。结果:114例乳腺癌组织中,97例阳性表达,阳性率达85.09%;92例非癌组织中,阳性表达10例,阳性率为10.87%,两组差异具有显著统计学意义（P＜0.001）。Amot在乳腺癌组织中高表达,定位在细胞核和胞浆中,主要定位于细胞核;组织芯片癌旁组织中低表达。MCF-7细胞系经Amot沉默后,细胞形态学上发生上皮间质表型转化。Amot基因沉默后,乳腺癌MCF-7干细胞相关分子表型标志CD24/CD44双标阳性率的变化:CON组:CD24（11.1±0.55）%、CD44<（0.1±0.48）%;NC组:CD24（12.4±0.62）%、CD44<（0.08±0.7）%;KD组:CD24<（0.1±0.08）%、CD44（81.0±2.02）%。乳腺癌干细胞相关分子表型标志物CD24表达降低,CD44表达明显增强,差异有统计学意义（P＜0.001）。肿瘤球形成率:CON组2.6%,NC组2.8%,KD组9.75%;乳腺癌细胞在Amot沉默后形成“肿瘤球”能力增强,差异具有统计学意义（P＜0.01）。干细胞特性相关基因C-myc、Sox-2表达增加;上皮蛋白E-cadherin表达减弱,间皮蛋白N-cadherin、Vimentin、a-SMA、Snail表达明显增加,差异均有统计学意义（P＜0.05）。同时发现,MCF-7细胞系经Amot 沉默后,Hippo-YAP通路中YAP及YAP/TAZ表达降低,YAP上游LATS1表达降低,差异有统计学意义（P＜0.01）。结论:Amot基因沉默增强乳腺癌干细胞特性,诱发乳腺癌细胞发生EMT。     

Immunohistochemical staining of cancer stem cell markers in hepatocellular carcinoma

Background

Cancer stem cells (CSCs) are thought to be a critical subpopulation in tumor development, progression, metastasis and recurrence, and the identification of these cells is an initial step in understanding their role in oncogenesis and in seeking valuable markers for diagnosis or development of targeting therapeutics.

Aims

To identify CSCs in hepatocellular carcinoma (HCC) specimens and define their tissue specificity.

Methods

Immunohistochemical staining of CSC markers: CD44, CD90, CD133 and aldehyde dehydrogenase (ALDH) was performed in 25 HCC specimens, 4 hepatoblastomas, 8 peri-malignant tissues, and 19 cases of viral hepatitis.

Results

The positivity of CD44 staining in HCC specimens was significantly lower than in viral hepatitis specimens. The positive rate of CD133 in HCC was similar to viral hepatitis specimens. CD133⁺ cells were largely localized to ALDH-positive cells in HCC as revealed by confocal microscopy. In contrast, the co-expression of both markers was visualized within vessels or in the portal areas in viral hepatitis. Moreover, among 7 liver specimens adjacent to HCC tissue, 3-6 samples were positive for CD44, CD90, CD133 and ALDH, especially in dysplastic cells. One of 4 hepatoblastoma cases was positive for all these markers; whereas, the other three specimens were negative for all these CSC markers.

Conclusions

In HCC and dysplastic tissues, clusters of CD133⁺/ALDH^high cells were identified. The use of cancer stem cell markers to screen tissues with chronic liver diseases provides limited guidance in the identification of malignant cells.