Efficacy of Whole Cancer Stem Cell-Based Vaccines: A Systematic Review of Preclinical and Clinical Studies.

Background: Despite the conventional cancer therapeutic, cancer treatment remains a medical challenge due to neoplasm metastasis and cancer recurrence; therefore, new approaches promoting therapeutic strategies are highly desirable. As a new therapy, the use of whole neoplastic stem cells or cancer stem cell (CSC)-based vaccines is one strategy to overcome these obstacles. We investigated the effects of whole CSC-based vaccines on the solid tumor development, metastasis, and survival rate.

Dendritic cells loaded with exosomes derived from cancer stem cell-enriched spheroids as a potential immunotherapeutic option.

Cancer stem cells (CSCs) are responsible for therapeutic resistance and recurrence in colorectal cancer. Despite advances in immunotherapy, the inability to specifically eradicate CSCs has led to treatment failure. Hence, identification of appropriate antigen sources is a major challenge in designing dendritic cell (DC)-based therapeutic strategies against CSCs.

Tumor-derived exosomes: the next generation of promising cell-free vaccines in cancer immunotherapy.

Identification of immunogenic tumor antigens that are efficiently processed and delivered by dendritic cells to prime the immune system and to induce an appropriate immune response is a research hotspot in the field of cancer vaccine development. High biosafety is an additional demand. Tumor-derived exosomes (TEXs) are nanosized lipid bilayer encapsulated vesicles that shuttle bioactive information to the tumor microenvironment facilitating tumor progression.

Exosomes, metastases, and the miracle of cancer stem cell markers.

Cancer-initiating cells (CIC) are the driving force in tumor progression. There is strong evidence that CIC fulfill this task via exosomes (TEX), which modulate and reprogram stroma, nontransformed cells, and non-CIC. Characterization of CIC, besides others, builds on expression of CIC markers, many of which are known as metastasis-associated molecules.

Pancreatic cancer-initiating cell exosome message transfer into noncancer-initiating cells: the importance of CD44v6 in reprogramming.

Background: Cancer-initiating cell (CIC) exosomes (CIC-TEX) are suggested reprogramming Non-CIC. Mode of message transfer and engagement of CIC-markers being disputed, we elaborated the impact of CD44v6 and Tspan8 on the response of Non-CIC.

Methods: Non-metastasizing CD44v6- and Tspan8-knockdown (kd) pancreatic cancer cells served as Non-CIC.

Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression.

Background: The tetraspanins Tspan8 and CD151 promote metastasis, exosomes (Exo) being suggested to be important in the crosstalk between tumor and host. The contribution of Tspan8 and CD151 to host versus tumor-derived exosome (TEX) activities being not defined, we approached the questions using 3-methylcholanthrene-induced (MCA) tumors from wt, Tspan8ko, CD151ko and Tspan8/CD151 (db)ko mice, implanted into tetraspanin-competent and deficient hosts.

Methods: Tumor growth and dissemination, hematopoiesis and angiogenesis were surveyed in wild type (wt), Tspan8ko, CD151ko and dbko mice bearing tetraspanin-competent and -deficient MCA tumors.

Therapeutic Targeting Cancer-Initiating Cell Markers by Exosome miRNA: Efficacy and Functional Consequences Exemplified for claudin7 and EpCAM.

Aim: Transfer of exosomes (Exo) miRNA was described interfering with tumor progression. We here explored for claudin7 (cld7) and EpCAM (EpC), cancer-initiating-cell markers in colorectal and pancreatic cancer, the efficacy of Exo loading with miRNA and miRNA transfer.

Methods: Exo were collected from nontransformed mouse (NIH3T3) and rat lung fibroblasts (rFb), which were transfected with Tspan8 cDNA (NIH3T3-Tspan8, rFb-Tspan8).

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression.

Metastasis is the leading cause of cancer death, tumor progression proceeding through emigration from the primary tumor, gaining access to the circulation, leaving the circulation, settling in distant organs and growing in the foreign environment. The capacity of a tumor to metastasize relies on a small subpopulation of cells in the primary tumor, so called cancer-initiating cells (CIC). CIC are characterized by sets of markers, mostly membrane anchored adhesion molecules, CD44v6 being the most frequently recovered marker.

Janus-Faced Myeloid-Derived Suppressor Cell Exosomes for the Good and the Bad in Cancer and Autoimmune Disease.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells originally described to hamper immune responses in chronic infections. Meanwhile, they are known to be a major obstacle in cancer immunotherapy. On the other hand, MDSC can interfere with allogeneic transplant rejection and may dampen autoreactive T cell activity.

Distorted leukocyte migration, angiogenesis, wound repair and metastasis in Tspan8 and Tspan8/CD151 double knockout mice indicate complementary activities of Tspan8 and CD51.

The tetraspanin Tspan8 supports via associated integrins and proteases tumor progression and angiogenesis. To shed light on its activities in non-transformed cells, we generated a Tspan8 knockout (ko) mouse, comparing leukocyte migration, angiogenesis, wound healing and tumor growth with wild type, CD151ko and Tspan8/CD151ko (dbko) mice. CD151ko mice were included as CD151 activities resemble that of Tspan8, and dbko mice to exclude mutual substitution.

Efficacy of vaccination with tumor-exosome loaded dendritic cells combined with cytotoxic drug treatment in pancreatic cancer.

Pancreatic cancer (PaCa) has a dismal prognosis and adjuvant immunotherapy frequently is of low efficacy due to immunosuppressive features of PaCa and PaCa-stroma. We here explored, whether the efficacy of vaccination with tumor-exosome (TEX)-loaded dendritic cells (DC) can be improved by combining with drugs affecting myeloid-derived suppressor cells (MDSC). Experiments were performed with the UNKC6141 PaCa line.

Murine and human pancreatic tumor exosome recovery in mouse serum: Diagnostic and prognostic potential and target cell delivery.

Exosomes (Exo), powerful intercellular communicators, are recovered in all body fluids, suggesting suitability for diagnosis and prognosis. Easy in vitro manipulation recommends Exo as drug vehicles. Aiming to consolidate diagnostic and therapeutic potential of Exo, we evaluated recovery and fate of tumor (TEX) and exogenous Exo in syngeneic and xenogeneic mice bearing a murine or a human pancreatic adenocarcinoma.

Joint features and complementarities of Tspan8 and CD151 revealed in knockdown and knockout models.

Tetraspanins are highly conserved 4-transmembrane proteins which form molecular clusters with a large variety of transmembrane and cytosolic proteins. By these associations tetraspanins are engaged in a multitude of biological processes. Furthermore, tetraspanin complexes are located in specialized microdomains, called tetraspanin-enriched microdomains (TEMs).

Pancreatic cancer stem cell markers and exosomes - the incentive push.

Pancreatic cancer (PaCa) has the highest death rate and incidence is increasing. Poor prognosis is due to late diagnosis and early metastatic spread, which is ascribed to a minor population of so called cancer stem cells (CSC) within the mass of the primary tumor. CSC are defined by biological features, which they share with adult stem cells like longevity, rare cell division, the capacity for self renewal, differentiation, drug resistance and the requirement for a niche.

CD44v6-competent tumor exosomes promote motility, invasion and cancer-initiating cell marker expression in pancreatic and colorectal cancer cells.

Cancer-initiating cells (CIC) account for metastatic spread, which may rely mostly on CIC exosomes (TEX) that affect host cells and can transfer CIC features into Non-CIC. The CIC marker CD44 variant isoform v6 (CD44v6) being known for metastasis-promotion, we elaborated in cells its contribution to migration and invasion and in TEX the tranfer of migratory and invasive capacity to Non-CIC, using a CD44v6 knockdown (CD44v6kd) as Non-CIC model.A CD44v6kd in human pancreatic and colorectal cancer (PaCa, CoCa) lines led to loss of CIC characteristics including downregulation of additional CIC markers, particularly Tspan8.

Progress and potential of exosome analysis for early pancreatic cancer detection.

Introduction: Pancreatic cancer (PaCa) is the most deadly malignancy, due to late diagnosis prohibiting surgery. Thus, strong efforts are taken improving early diagnosis via biomarkers recovered in the serum of PaCa patients.

Areas Covered: One promising option are PaCa-derived exosomes in patients' sera.

Palmitoylated claudin7 captured in glycolipid-enriched membrane microdomains promotes metastasis via associated transmembrane and cytosolic molecules.

In epithelial cells claudin7 (cld7) is a major component of tight junctions, but is also recovered from glycolipid-enriched membrane microdomains (GEM). In tumor cells, too, cld7 exists in two stages. Only GEM-located cld7, which is palmitoylated, promotes metastasis.

Exosomes in Cancer Disease.

Cancer diagnosis and therapy is steadily improving. Still, diagnosis is frequently late and diagnosis and follow-up procedures mostly are time-consuming and expensive. Searching for tumor-derived exosomes (TEX) in body fluids may provide an alternative, minimally invasive, yet highly reliable diagnostic tool.

CD44, Hyaluronan, the Hematopoietic Stem Cell, and Leukemia-Initiating Cells.

CD44 is an adhesion molecule that varies in size due to glycosylation and insertion of so-called variant exon products. The CD44 standard isoform (CD44s) is highly expressed in many cells and most abundantly in cells of the hematopoietic system, whereas expression of CD44 variant isoforms (CD44v) is more restricted. CD44s and CD44v are known as stem cell markers, first described for hematopoietic stem cells and later on confirmed for cancer- and leukemia-initiating cells.