The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis

Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy.     

Cancer drug resistance: A fleet to conquer

Cancer is a disease that claims millions of lives each year across the world. Despite advancement in technologies and therapeutics for treating the disease, these modes are often found to turn ineffective during the course of treatment. The resistance against drugs in cancer patients stems from multiple factors, which constitute genetic heterogeneity like gene mutations, tumor microenvironment, exosomes, miRNAs, high rate of drug efflux from cells, and so on. This review attempts to collate all such known and reported factors that influence cancer drug resistance and may help researchers with information that might be useful in developing better therapeutics in near future to enable better management of several cancers across the world.     

The mesenchymal tumor microenvironment: A drug-resistant niche

Drug and radiation resistance represent a challenge for most anticancer therapies. Diverse experimental approaches have provided evidence that the tumor-associated microenvironment constitutes both a protective shell that impedes drug or radiation access and a permissive or promotive microenvironment that encourages a nurturing cancer (i.e., cancer stem cell) niche where tumor cells overcome treatment- and cancer-induced stresses. Better understanding of the effects of the tumor microenvironment on cancer cells before, during and immediately after chemo- or radiotherapy is imperative to design new therapies aimed at targeting this tumor-protective niche. This review summarizes some of the known mesenchymal stromal effects that account for drug resistance, the main signal transduction pathways associated with this resistance and the therapeutic efforts directed to increase the success of current therapies. Special emphasis is given to environment-mediated drug resistance in general and to cell adhesion-mediated drug resistance in particular.     

Colon cancer therapy by focusing on colon cancer stem cells and their tumor microenvironment

Despite many advances and optimization in colon cancer treatment, tumor recurrence and metastases make the development of new therapies necessary. Colon cancer stem cells (CCSCs) are considered as the main triggering factor of cancer progression, recurrence, and metastasis. CCSCs as a result of accumulated genetic and epigenetic alterations and also complex interconnection with the tumor microenvironment (TME) can evolve and convert to full malignant cells. Mounting evidence suggests that in cancer therapy both CCSCs and non-CCSCs in TME have to be regarded to break through the limitation of current therapies. In this regard, stem cell capabilities of some non-CCSCs may arise inside the TME condition. Therefore, a deep knowledge of regulatory mechanisms, heterogeneity, specific markers, and signaling pathways of CCSCs and their interconnection with TME components is needed to improve the treatment of colorectal cancer and the patient's life quality. In this review, we address current different targeted therapeutic options that target cell surface markers and signaling pathways of CCSCs and other components of TME. Current challenges and future perspectives of colon cancer personalized therapy are also provided here. Taken together, based on the deep understanding of biology of CCSCs and using three-dimensional culture technologies, it can be possible to reach successful colon cancer eradication and improvise combination targeted therapies against CCSCs and TME.     

The hypoxic microenvironment: A determinant of cancer stem cell evolution

Tumors are often viewed as unique entities with specific behaviors. However, tumors are a mixture of differentially evolved subpopulations of cells in constant Darwinian evolution, selecting the fittest clone and allowing it to outgrow the rest. As in the natural environment, the niche defines the properties the fittest clones must possess. Therefore, there can be multiple fit clones because of the various microenvironments inside a single tumor. Hypoxia is considered to be a major feature of the tumor microenvironment and is a potential contributor to the cancer stem cell (CSC) phenotype and its enhanced tumorigenicity. The acidic microenvironment around hypoxic cells is accompanied by the activation of a subset of proteases that contribute to metastasis. Because of aberrant angiogenesis and the inaccessibility of their locations, hypoxic cells are less likely to accumulate therapeutic concentrations of chemotherapeutics that can lead to therapeutic resistance. Therefore, the targeting of the hypoxic CSC niche in combination with chemotherapy may provide a promising strategy for eradicating CSCs. In this review, we examine the cancer stem cell hypothesis and its relationship to the microenvironment, specifically to hypoxia and the subsequent metabolic switch and how they shape tumor behavior.     

Spatial CRISPR genomics identifies regulators of the tumor microenvironment

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Progress of Breast Cancer basic research in China

Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese investigators have recently made new discoveries in basic breast cancer researches, especially regarding cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this review, we summarized the latest important findings in this field in China.     

Combined therapy of p53-wt and drug in an orthotopic multidrug-resistant human lung cancer model

Balb/c nu/nu mice were inoculated intratracheally with multidrug-resistant human lung cancer cells GLK containing p53 mutation at codon 245 and treated with intratracheal instillation of p53-wt retroviral vector (pDOR53W) to increase cell chemosensitivity, and then with intraperitoneal injection of doxorubicin. 30 d after tumor cell inoculation, 75% of the control mice showed macroscopic tumors in the lung. Sole pDOR53W suppressed GLK tumor formation in 68 % of mice; sole doxorubicin 33. 3 % , but the combination of pDOR53W and doxorubicin 88.9%. The exogenous p53 sequence was detected and confirmed in the tumor that grew after treatment with pDOR53W retroviral vector by PCR and Southern blot hybridization with p53 cDNA. These results suggested that di-rect administration of a retroviral vector expressing p53-wt combined with treatment of anticancer agent was an effec-tive therapeutic method for multidrug-resistant human lung cancer.     

The exploration of new therapeutic targets for HPV-negative head and neck squamous cell cancer through the construction of a ceRNA network and immune microenvironment analysis

Previous studies have shown that human papillomavirus (HPV)-negative patients with head and neck squamous cell cancer (HNSCC) suffer from an unsatisfactory prognosis. Long noncoding RNAs (lncRNAs) have been verified to participate in many biological processes, including regulating gene expression as competing endogenous RNAs (ceRNAs), while few studies focused the ceRNA network regulation mechanism in patients with HPV-negative HNSCC tumor. Meanwhile, the immune microenvironment may be critical in the development and prognosis of HPV-negative tumors. Our study aimed to further investigate the pathogenesis and potential biomarkers for the diagnosis, therapy and prognosis of HPV-negative HNSCC through a ceRNA network. Comprehensively analyzing the sequencing data of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) in The Cancer Genome Atlas HNSCC dataset, we constructed a differentially expressed ceRNA network containing 131 lncRNAs, 35 miRNAs and 162 mRNAs. Then, survival analysis in the network was cited to explore the prognostic biomarkers. Eight mRNAs, nine lncRNAs, and one miRNA were identified to be associated with prognosis. Neuropilin (NRP) binding function, retinoid X receptor (RXR) binding, and the vascular endothelial growth factor (VEGF) signaling pathway were associated with the enrichment analysis, and they also related to the immune microenvironment. Combined with the analysis of the immune microenvironment differences, we obtained new targeted therapies using an RXR agonist, or a combination of the VEGF monoclonal antibody and an NRP antagonist, which may provide a promising future for HPV-negative HNSCC patients.     

The Multifaceted Role of Long Non-Coding RNA in Gastric Cancer: Current Status and Future Perspectives

Gastric cancer (GC) is one of the major public health concerns. Long non-coding RNAs (lncRNAs) have been increasingly demonstrated to possess a strong correlation with GC and play a critical role in GC occurrence, progression, metastasis and drug resistance. Many studies have shed light on the understanding of the underlying mechanisms of lncRNAs in GC. In this review, we summarized the updated research about lncRNAs in GC, focusing on their roles in Helicobacter pylori infection, GC metastasis, tumor microenvironment regulation, drug resistance and associated signaling pathways. LncRNAs may serve as novel biomarkers for diagnosis and prognosis of GC and potential therapeutic targets. The research gaps and future directions were also discussed.     

Interactive functions of microRNAs in the miR-23a-27a-24-2 cluster and the potential for targeted therapy in cancer

MicroRNAs (miRNAs) are small noncoding RNAs about 19–22 nucleotides in length. Growing evidence has reported the significant role of miRNAs in various cancer-associated biological processes, such as proliferation, differentiation, apoptosis, metabolism, invasion, metastasis, and drug resistance. However, most studies focus on the targets of some individual miRNAs; the interactive and global functions of diverse miRNAs are still unclear and the phenomenon of the gathering of miRNAs in clusters has always been ignored. On the other hand, the fact that a single miRNA may regulate many genes and that numerous mRNAs are regulated by the same miRNA also makes it imperative to further study the cooperating characteristics of miRNAs in cancer. MiR-23a-27a-24-2 is located in the human chromosome 9q22, forming three mature miRNAs: miR-23a, miR27a, and miR-24, which are expressed abnormally in many malignant tumors. This review aims to summarize the interactive functions of miRNAs in miR-23a-27a-24-2 clusters in cancer from the perspectives of the regulation network, tumor microenvironment, and targeted therapy.     

A multivariate model of ErbB network composition predicts ovarian cancer cell response to canertinib

Identifying the optimal treatment strategy for cancer is an important challenge, particularly for complex diseases like epithelial ovarian cancer (EOC) that are prone to recurrence. In this study we developed a quantitative, multivariate model to predict the extent of ovarian cancer cell death following treatment with an ErbB inhibitor (canertinib, CI-1033). A partial least squares regression model related the levels of ErbB receptors and ligands at the time of treatment to sensitivity to CI-1033. In this way, the model mimics the clinical problem by incorporating only information that would be available at the time of drug treatment. The full model was able to fit the training set data and was predictive. Model analysis demonstrated the importance of including both ligand and receptor levels in this approach, consistent with reports of the role of ErbB autocrine loops in EOC. A reduced multi-protein model was able to predict CI-1033 sensitivity of six distinct EOC cell lines derived from the three subtypes of EOC, suggesting that quantitatively characterizing the ErbB network could be used to broadly predict EOC response to CI-1033. Ultimately, this systems biology approach examining multiple proteins has the potential to uncover multivariate functions to identify subsets of tumors that are most likely to respond to a targeted therapy.     

A four-gene signature predicts the efficacy of paclitaxel-based neoadjuvant therapy in human epidermal growth factor receptor 2–negative breast cancer

Neoadjuvant chemotherapy (NAC) is the major preoperative treatment of breast cancer (BC) with negative human epidermal growth factor receptor 2 (HER2), and the efficacy of NAC and the optimization of regimen are under intensive research. The current study aimed to define the predictive biomarkers for paclitaxel (PTX) response in NAC of HER2-negative BC. Data from GSE25065, GSE26065, GSE41998, as well as drug sensitivity data of breast and ovarian cancer cell line from NCI60, were used. Through logistic regression, COX regression, and correlation analysis with bootstrapping, we found that four genes (CDK8, FAM64A, MARC2, and OCEL1) were associated with drug sensitivity of PTX. The four gene “≥3” model had the best classification accuracy. Subgroup analysis found that the model performed well in the hormone receptor positive, HER2-negative subgroup and did not perform well in the triple-negative subgroup. Decision curve analysis showed that the model could enhance the predictive effect of clinical features. Subsequent gene set enrichment analysis, network analysis showed that these genes may be related to the cell cycle, mitosis and other pathways. The current study demonstrated the promising potential of the novel four-gene signature as a predictive biomarker for pathological complete response of HER2-negative BC patients and indicated the drug sensitivity of PTX.     

Evolution of Relapse-Proficient Subclones Constrained by Collateral Sensitivity to Oncogene Overdose in Wnt-Driven Mammary Cancer

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Processing and characterization of the low density lipoprotein receptor in the human colonic carcinoma cell subclone HT29-18: A potential pathway for delivering therapeutic drugs and genes

Low density lipoprotein (LDL) processing has been investigated in the subcloned human colonic carcinoma cell line HT29-18. LDL binding at 4°C was a saturable process in relation to time and LDL concentration. The Kd for LDL binding was 11 g/ml. ApoE-free HDL₃ or acetylated LDL did not significantly compete with¹²⁵I-LDL binding, up to 500 g/ml.¹²⁵I-LDL binding was decreased by 70% in HT29-18 cells preincubated for 24 hours in culture medium containing 100 g/ml unlabelled LDL. Ligand blotting studies performed on HT29-18 homogenates using colloidal gold labelled LDL indicated the presence of one autoradiographic band corresponding to an apparent molecular weight of 130 kDa, which is consistent with the previously reported molecular weight of the LDL receptor in human fibroblasts. At 37°C,¹²⁵I-LDL was actively internalized by HT29-18 cells and lysosomal degradation occurred as demonstrated by the inhibitory effect of chloroquine. LDL uptake and degradation by HT29-18 cells also resulted in a marked decrease in endogenous sterol synthesis. These data demonstrate that the HT29-18 human cancerous intestinal cells are able to specifically bind and internalize LDL, and that LDL processing results in down-regulation of sterol biosynthesis. Thus, intestinal epithelial cells possess specific LDL receptors that can be exploited to accomplish drug delivery and gene transfer via the receptor-mediated endocytosis pathway.Abbreviations HDL, HCL₃ high density lipoprotein - LDL low density lipoprotein     

High-dose neoadjuvant chemoradiotherapy versus chemotherapy alone followed by surgery in potentially-resectable stage IIIA-N2 NSCLC. A multi-institutional retrospective study by the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society)

BackgroundThe optimal induction treatment in potentially-resectable stage IIIA-N2 NSCLC remains undefined.AimTo compare neoadjuvant high-dose chemoradiotherapy (CRT) to neoadjuvant chemotherapy (CHT) in patients with resectable, stage IIIA-N2 non-small-cell lung cancer (NSCLC).MethodsRetrospective, multicentre study of 99 patients diagnosed with stage cT1-T3N2M0 NSCLC who underwent neoadjuvant treatment (high-dose CRT or CHT) followed by surgery between January 2005 and December 2014.Results47 patients (47.5%) underwent CRT and 52 (52.5%) CHT, with a median follow-up of 41 months. Surgery consisted of lobectomy (87.2% and 82.7%, in the CRT and CHT groups, respectively) or pneumonectomy (12.8% vs. 17.3%). Nodal downstaging (to N1/N0) and Pathologic complete response (pCR; pT0pN0) rates were significantly higher in the CRT group (89.4% vs. 57.7% and 46.8% vs. 7.7%, respectively; p < 0.001)). Locoregional recurrence was significantly lower in the CRT group (8.5% vs. 13.5%; p = 0.047) but distant recurrence rates were similar in the two groups. Median PFS was 45 months (CHT) vs. “not reached” (CRT). Median OS was similar: 61 vs. 56 months (p = 0.803). No differences in grade ≥3 toxicity were observed. On the Cox regression analysis, advanced pT stage was associated with worse OS and PFS (p < 0.001) and persistent N2 disease (p = 0.002) was associated with worse PFS.ConclusionsCompared to neoadjuvant chemotherapy alone, a higher proportion of patients treated with preoperative CRT achieved nodal downstaging and pCR with better locoregional control. However, there were no differences in survival. More studies are needed to know the optimal treatment of these patients.