Therapeutic Targeting of Tumor Cells Rich in LGR Stem Cell Receptors

Melanoma releases numerous tumor cells into the circulation; however, only a very small fraction of these cells is able to establish distant metastasis. Intravascular survival of circulating tumor cells is limited through hemodynamic forces and by the lack of matrix interactions. The extravasation step is, thus, of unique importance to establish metastasis. Similar to leukocyte extravasation, this process is under the control of adhesion molecule pairs expressed on melanoma and endothelial cells, and as for leukocytes, ligands need to be adequately presented on cell surfaces. Based on melanoma plasticity, there is considerable heterogeneity even within one tumor and one patient resulting in a mixture of invasive or proliferative cells. The molecular control for this switch is still ill-defined. Recently, the balance between two kinase pathways, p38 and JNK, has been shown to determine growth characteristics of melanoma. While an active JNK pathway induces a proliferative phenotype with reduced invasive features, an active p38/MK2 pathway results in an invasive phenotype and supports the extravasation step via the expression of molecules capable of binding to endothelial integrins. Therapeutic targeting of MK2 to prevent extravasation might reduce metastatic spread.

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A Potential Antitumor Effect of Dendritic Cells Fused with Cancer Stem Cells in Hepatocellular Carcinoma

Stem Cells International ◽

10.1155/2019/5680327 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Ye-Bin Pang ◽

Jian He ◽

Bi-Yu Cui ◽

Sheng Xu ◽

Xi-Lei Li ◽

...

Keyword(s):

Stem Cells ◽

Dendritic Cells ◽

Stem Cell ◽

Tumor Cells ◽

Hepg2 Cells ◽

Cytotoxicity Assay ◽

Tumor Stem Cell ◽

Fusion Cell

HCC stem cells were reported as posttreatment residual tumor cells that play a pivotal role in tumor relapse. Fusing dendritic cells (DCs) with tumor cells represents an ideal approach to effectively activate the antitumor immunity in vivo. DC/HCC stem cell vaccine provides a potential strategy to generate polyclonal immune response to multiple tumor stem cell antigens including those yet to be unidentified. To assess the potential capacity of DC/HCC stem cell vaccines against HCC, CD90+HepG2 cells were sorted from the HCC cell line HepG2. DC and CD90+HepG2 and DC and HepG2 fused cells were induced by polyethylene glycol (PEG). The influence of fusion cells on proliferation and immunological function transformation of lymphocytes was assessed by FCM and ELISA assay, respectively. The cytotoxicity assay of specific fusion cell-induced CTLs against HepG2 was conducted by CytoTox 96 Non-Radioactive Cytotoxicity Assay kit in vitro. At last, the prevention of HCC formation in vivo was described in a mouse model. The results of FCM analysis showed that the proportion of CD90+HepG2 cells in the spheral CD90+HepG2 enriched by suspension sphere culture was ranging from 98.7% to 99.5%, and 57.1% CD90+HepG2/DC fused cells were successfully constructed. The fusion cells expressed a higher level of costimulatory molecules CD80, CD83, CD86, and MHC-I and MHC-II molecules HLA-ABC and HLA-DR than did immature DCs (P<0.05). And the functional analysis of fusion cell-induced CTLs also illustrated that CD90+HepG2/DC fusion cells showed a greater capacity to activate proliferation of lymphocytes in vitro (P<0.05). The CD90+HepG2/DC-activated CTLs had a specific killing ability against CD90+HepG2 cells in vivo. These results suggested that CD90+HepG2/DC fusion cells could efficiently stimulate T lymphocytes to generate specific CTLs targeting CD90+HepG2 cells. It might be a promising strategy of immunotherapy for HCC.

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Autologous transplantation of ex vivo expanded bone marrow cells grown from small aliquots after high-dose chemotherapy for breast cancer

Blood ◽

10.1182/blood.v95.6.2169 ◽

2000 ◽

Vol 95 (6) ◽

pp. 2169-2174 ◽

Cited By ~ 65

Author(s):

Patrick Stiff ◽

Bohao Chen ◽

Wilbur Franklin ◽

David Oldenberg ◽

Eric Hsi ◽

...

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Stem Cell ◽

Tumor Cell ◽

Tumor Cells ◽

Ex Vivo ◽

Autologous Transplantation ◽

High Dose Chemotherapy ◽

High Dose ◽

Small Aliquot

Abstract The collection of small aliquots of bone marrow (BM), followed by ex vivo expansion for autologous transplantation may be less morbid, and more cost-effective, than typical BM or blood stem cell harvesting. Passive elimination of contaminating tumor cells during expansion could reduce reinoculation risks. Nineteen breast cancer patients underwent autotransplants exclusively using ex vivo expanded small aliquot BM cells (900-1200 × 106). BM was expanded in media containing recombinant flt3 ligand, erythropoietin, and PIXY321, using stromal-based perfusion bioreactors for 12 days, and infused after high-dose chemotherapy. Correlations between cell dose and engraftment times were determined, and immunocytochemical tumor cell assays were performed before and after expansion. The median volume of BM expanded was 36.7 mL (range 15.8-87.0). Engraftment of neutrophils greater than 500/μL and platelets greater than 20 000/μL were 16 (13-24) and 24 (19-45) days, respectively; 1 patient had delayed platelet engraftment, even after infusion of back-up BM. Hematopoiesis is maintained at 24 months, despite posttransplant radiotherapy in 18 of the 19 patients. Transplanted CD34+/Lin−(lineage negative) cell dose correlated with neutrophil and platelet engraftment, with patients receiving greater than 2.0 × 105 CD34+/Lin− cells per kilogram, engrafting by day 28. Tumor cells were observed in 1 of the 19 patients before expansion, and in none of the 19 patients after expansion. It is feasible to perform autotransplants solely with BM cells grown ex vivo in perfusion bioreactors from a small aliquot. Engraftment times are similar to those of a typical 1000 to 1500 mL BM autotransplant. If verified, this procedure could reduce the risk of tumor cell reinoculation with autotransplants and may be valuable in settings in which small stem cell doses are available, eg, cord blood transplants.

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