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Compositions and methods for increasing mesenchymal stromal cell migration to tumors

a mesenchymal stromal cell and tumor technology, applied in the field of compositions and methods for increasing the migration of mesenchymal stromal cells to tumors, can solve the problems of only being able to apply to a minority of patients, and the mechanisms involved in the recruitment of mscs to tumors in general, and achieve the effect of increasing the migration of mscs and increasing the adhesion of mscs

Inactive Publication Date: 2016-08-04
ROSIVO LLC +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about combining cellular and gene therapy to treat cancer. Specifically, it describes using cells called mesenchymal stromal cells (MSCs) that have been modified to carry therapeutic genes, such as an anti-tumor agent, and stimulating those cells with a specific protein called autocrine motility factor (rAMF). The patent also discusses methods for encouraging the MSCs to attach to endothelial cells. Overall, this approach presents a potential way to target tumorous areas with specific gene therapy and improve the effectiveness of cell-based therapies for cancer treatment.

Problems solved by technology

However, the mechanisms involved in MSCs recruitment to tumors in general, and to specific tumors, e.g., hepatocellular carcinoma (HCC), are not fully understood.
(2012) J Hepatol 56 Suppl 1: S75-87); however, these strategies can only be applied to a minority of patients.

Method used

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  • Compositions and methods for increasing mesenchymal stromal cell migration to tumors
  • Compositions and methods for increasing mesenchymal stromal cell migration to tumors
  • Compositions and methods for increasing mesenchymal stromal cell migration to tumors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Materials and Methods

Cell Lines

[0092]Human HCC cell line HuH7 were kindly provided by Prof. Jesus Prieto (CIMA, University of Navarra, Pamplona, Spain). LX-2 cell line (human HSCs generated by spontaneous immortalization in low serum conditions) was kindly provided by Dr. Scott Friedman (Division of Liver Diseases, Mount Sinai School of Medicine, New York, N.Y., USA). Human microvascular endothelial cells (HMEC-1) were provided by CDC (Centers for Disease Control, Atlanta, Ga., USA). Cell lines were cultured in complete DMEM (2 μmol / L glutamine, 100 U / mL penicillin, 100 mg / mL streptomycin and 10% heat-inactivated fetal bovine serum (FBS)). Primary culture of HCC cells (HC-PT-5) was previously generated in our laboratory and cultured the eight passage in 70% DMEM / 30% F12 (Invitrogen / Life Technologies) culture medium supplemented with 2 μmol / L glutamine, 100 units / mL penicillin, 100 mg / mL streptomycin and 10% FBS.

Isolation of MSCs, AT-MSCs and Mesenchymal Cells Harvested from Umbilica...

example 2

Identification of Secreted Factors from HCC Microenvironment

[0111]Factors secreted from hepatocellular carcinoma (HCC) microenvironment were identified. Tumor conditioned media (TCM) were obtained from fresh HCC samples or tumors generated from primary cultured human HCC cells (HC-PT-5) or the HuH7 cell line in BALB / c nude mice.

[0112]In vitro migratory capacity of MSCs to different TCM samples was analyzed using a 48-Transwell microchemotaxis Boyden Chamber unit (Neuroprobe, Inc.).

[0113]Factors present in the different TCM were identified using two Human Cytokine and Chemokine Antibody Arrays (RayBiotech). The factors identified are shown in Tables 1 and 2.

[0114]Changes in the gene expression patterns in MSCs exposed to TCM derived from HCC samples were also analyzed. MSCs were exposed overnight to TCM or DMEM (as control) and studied using a microarray gene expression analysis with the aim to identify genes that were differentially expressed in MSCs exposed or not to TCM. Table 3 s...

example 3

Recombinant AMF Exerts a Specific Chemoatractant Activity on MSCs from Different Sources

[0117]The tumor conditioned media (TCM) from ex vivo subcutaneous (s.c.) tumors derived from HuH7 cell line or HC-PT-5 HCC primary culture and conditioned media from cell culture monolayers (CCM) were subjected to western blot analysis according to the method described in Example 1. A 55 kDa soluble AMF was detected in CCM and TCM (FIG. 2A).

[0118]The ability of recombinant human AMF (rAMF) to induce MSCs chemotaxis in vitro was analyzed. MSCs from different sources were evaluated by in vitro migration assay with modified Boyden chambers as described in Example 1. Human MSCs derived from bone marrow (BM-MSCs), perivascular umbilical cord region (Mesenchymal cells harvested from umbilical cord perivascular tissue), or adipose tissue (AT-MSCs) were used in a modified Boyden chamber assay.

[0119]The MSCs from the different sources migrated in a dose-dependent manner towards recombinant AMF (FIG. 2B-D)...

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PUM

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Abstract

The present application is directed to compositions and methods for treating a subject with cancer and / or increasing migration of a mesenchymal stromal cells (MSCs) stimulated with a recombinant autocrine motility factor (rAMF) to a tumor or a tumor cell, e.g. hepatocellular carcinoma (HCC). In addition, methods for increasing adhesion of MSCs to endothelial cells with rAMF are disclosed. In some embodiments, the MSCs comprise a therapeutic agent, e.g., an anti-tumor agent.

Description

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY[0001]The content of the electronically submitted sequence listing in ASCII text file (Name: “3181_006PC01_SequenceListing.ascii”; Size: 10,549; and Date of Creation: Sep. 4, 2014) filed with the application is incorporated herein by reference in its entirety.BACKGROUND[0002]Mesenchymal stromal cells (MSCs) (also referred to as fibroblastic colony forming units or mesenchymal stem cells) constitute a heterogeneous cell population, characterized by their adherence to plastic, fibroblast-like morphology, expression of specific markers (e.g., CD105+, CD90+, CD73+), lack of hematopoietic markers (e.g., CD45, CD34, CD14 or CD11b, CD79a or CD19) and HLA class II and capability to differentiate in vitro into osteoblasts, adipocytes and chondroblasts (Dominici, M., K. Le Blanc, et al. (2006) Cytotherapy 8(4): 315-317). MSCs are most often derived from bone marrow (BM), but can also be isolated from adipose tissue (AT) or from umbilical c...

Claims

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Application Information

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IPC IPC(8): A61K35/28C12N5/077
CPCC12N5/0605C12N5/0668C12N2501/20C12N2501/40A61K35/28C12N5/0669C12N2501/998C12N2502/99A61P35/00
Inventor MAZZOLINI, GUILLERMO DANIELGARCIA, MARIANA GABRIELABAYO, JUAN
Owner ROSIVO LLC
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