Nonheritable Cellular Variability Accelerates the Evolutionary Processes of Cancer

Heritable genetic or epigenetic changes in cells are thought to drive tumor development, metastasis, and drug resistance. This essay discusses the possibility that nonheritable phenotypic variability contributes to the evolution of cancer, suggesting new approaches to treatment

The Role of Extracellular Vesicles as Modulators of the Tumor Microenvironment, Metastasis and Drug Resistance in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide, with high morbidity and mortality rates. A number of factors including modulation of the tumor microenvironment, high metastatic capability, and resistance to treatment have been associated with CRC disease progression. Recent studies have documented that tumor-derived extracellular vesicles (EVs) play a significant role in intercellular communication in CRC via transfer of cargo lipids, proteins, DNA and RNAs to the recipient tumor cells. This transfer influences a number of immune-related pathways leading to activation/differentiation/expression of immune cells and modulation of the tumor microenvironment that plays a significant role in CRC progression, metastasis, and drug resistance. Furthermore, tumor-derived EVs are secreted in large amounts in biological fluids of CRC patients and as such the expression analysis of EV cargoes have been associated with prognosis or response to therapy and may be a source of therapeutic targets. This review aims to provide a comprehensive insight into the role of EVs in the modulation of the tumor microenvironment and its effects on CRC progression, metastasis, and drug resistance. On the other hand, the potential role of CRC derived EVs as a source of biomarkers of response and therapeutic targets will be discussed in detail to understand the dynamic role of EVs in CRC diagnosis, treatment, and management

Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance.

Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate.Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets

Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic and inflammatory microenvironment that is formed primarily by activated, myofibroblast-like, stellate cells. Although the stellate cells are thought to contribute to tumorigenesis, metastasis and drug resistance of PDAC, the signaling events involved in activation of the stellate cells are not well defined. Functioning as transcription co-factors, Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) modulate the expression of genes involved in various aspects of cellular functions, such as proliferation and mobility. Using human tissues we show that YAP and TAZ expression is restricted to the centroacinar and ductal cells of normal pancreas, but is elevated in cancer cells. In particular, YAP and TAZ are expressed at high levels in the activated stellate cells of both chronic pancreatitis and PDAC patients as well as in the islets of Langerhans in chronic pancreatitis tissues. Of note, YAP is up regulated in both acinar and ductal cells following induction of acute and chronic pancreatitis in mice. These findings indicate that YAP and TAZ may play a critical role in modulating pancreatic tissue regeneration, neoplastic transformation, and stellate cell functions in both PDAC and pancreatitis

Signaling Pathways Associated with Cancer Stem Cells Play a Significant Role in Immunotherapy Resistance

Cancer stem cells (CSCs) are a subpopulation of tumor cells with properties of self-renewal, pluripotency, plasticity, and differentiation, and are associated with various aberrantly stimulated signaling pathways. They are responsible for tumor recurrence, distant metastasis, and drug resistance, thus inducing poor prognosis. Immunotherapy has achieved encouraging results. However, the resistance associated with its clinical application is a persistent problem in clinical and scientific researches. Increasing evidence shows that signaling pathways associated with CSCs mediate immunotherapy resistance. This review highlights the link between them, and focuses on the underlying mechanism so as to provide potential strategies and approaches for the development of new targets against the immune resistance challenge

Characterization of Murine Breast Cancer Cell Lines for Anti-Cancer Vaccine

Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer death among women in the United States (1). While treatments involving radiation and chemotherapy currently exist, disease must be detected early in order for the treatments to be somewhat effective, and there is no effective treatment after metastasis occurs (2). Additionally, current therapies do not mitigate tumor immunosuppression. Decreasing the tumor-associated immunosuppressive conditions while activating antitumor immunity could prevent recurrence and metastasis, possibly leading to an effective treatment for cancer (3). Tumor cell vaccines could possibly address this issue and have become a recent topic of research. They have the potential to generate tumor regression and antitumor immune responses, but they have had low clinical response rates and poor immunogenicity so far (3, 4). We suspect the failure of cancer vaccines to be due to the immunosuppression and heterogeneity of breast cancers. Thus, to determine how and why different breast cancers induce different levels of immunosuppression, we studied different cancer cell lines of varying levels of immunogenicity. The study included five murine breast cancer cell lines, 4T1, 4T07, 66cl4, 168FARN, and 67NR. These are sister cell lines that were isolated from a Balb/cfC3H mouse and that differ in aggressiveness and metastatic capability. The production of immunosuppressive cytokines GM-CSF, G-CSF, M-CSF, IL-6, MCP-1, TGF-β, and VEGF was quantified for each of these cell lines. We also studied the effect these cytokines have on the expansion of myeloid-derived suppressor cells (MDSCs), which are known to suppress the immune response, and found that high levels of G-CSF are correlated with high numbers of MDSCs. A correlation between G-CSF levels and MDSC accumulation in these breast cancer cell lines could lead to future studies in which the effects of G-CSF are blocked in order to develop effective autologous breast cancer vaccines

Crippling Rapid Evolution of Metastasis and Drug Resistance in A549 Non-Small Cell Lung Cancer Cells with the Clinically Relevant HSP90 Inhibitor AUY922

The ability for species to evolve new features in response to changing circumstances in order to survive and propagate is a ubiquitous observation on both the macroscopic and microscopic levels of living systems. It should be no surprise, then, that diseases such as cancer utilize their own forms of adaptation to perpetuate themselves when exposed to external threats. Indeed, concepts drawn from Darwinian evolution are now widely accepted to help explain certain aspects of carcinogenesis and malignant progression, the sum of which have come to be known as the theory of tumor evolution. Since metastasis and drug resistance are features that manifest toward the late stages in the disease after withstanding numerous selective pressures, cancer cells harboring these features can be viewed as the most evolutionarily fit. Just as many forms of life rely on common adaptive mechanisms to promote their survival during dramatic shifts in their environment, metastatic and drug resistant cancers may rely upon common cellular mechanisms to promote their survival when faced with untenable circumstances. We hypothesize that one of the oldest genes in the human genome, HSP90, functions as a link between metastatic and drug resistant behavior of cancer. We believe this occurs through HSP90’s relationship in supporting the function of gene products that define the cancer hallmarks and clinical evidence suggesting HSP90 is important in progressing cancer into advanced stages. In the following chapters we discuss HSP90 and its role in orchestrating evolution of metastatic and drug resistant phenotypes. We use the clinically relevant HSP90 inhibitor, AUY922, to explore our assertions in vitro in the context of non-small cell lung cancer (NSCLC), which is prone to evolving metastatic and drug resistant phenotypes. We examine the implications for our findings, future directions, and new possibilities for utilizing HSP90 inhibitors to treat cancer

Exosomes promote pre-metastatic niche formation in ovarian cancer.

Ovarian cancer is one of the most common gynecological malignancies. Upon initial diagnosis, the majority of patients present with widespread metastatic growth within the peritoneal cavity. This metastatic growth occurs in stages, with the formation of a pre-metastatic niche occurring prior to macroscopic tumor cell invasion. Exosomes released by the primary ovarian tumor are small extracellular vesicles which prepare the distant tumor microenvironment for accelerated metastatic invasion. They regulate intercellular communication between tumor cells and normal stroma, cancer-associated fibroblasts, and local immune cells within the tumor microenvironment. In this review, we highlight the emerging roles of ovarian cancer exosomes as coordinators of pre-metastatic niche formation, biomarkers amenable to liquid biopsy, and targets of chemotherapy