Compositions and methods for increasing mesenchymal stromal cell migration to tumors

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.

1 . A composition comprising a mesenchymal stromal cell (MSC) stimulated with a recombinant autocrine motility factor (rAMF), wherein the MSC comprises a therapeutic agent and wherein the MSC of the composition has (1) increased migration to a tumor or a tumor cell after rAMF stimulation and/or (2) increased adhesion to an endothelial cell after rAMF stimulation. 
     
     
         2 . The composition of  claim 1 , wherein the endothelial cell is a vascular endothelial cell. 
     
     
         3 . The composition of  claim 1 , wherein the tumor is a solid tumor. 
     
     
         4 . The composition of  1 , wherein the tumor is a cancer selected from the group consisting of a liver cancer, a colon cancer, a pancreatic cancer, a lung cancer, a gastrointestinal cancer, a kidney cancer, or a breast cancer. 
     
     
         5 . The composition of  claim 1 , wherein the tumor is a carcinoma. 
     
     
         6 . The composition of  claim 5 , wherein the carcinoma is hepatocellular carcinoma (HCC). 
     
     
         7 . The composition of  claim 5 , wherein carcinoma is colorectal carcinoma. 
     
     
         8 . The composition of  claim 1 , wherein the tumor or the tumor cell expresses endogenous AMF. 
     
     
         9 . The composition of  claim 1 , wherein the increased migration and or adhesion is two-fold greater than migration and or adhesion of the MSC without rAMF stimulation. 
     
     
         10 . The composition of  claim 1 , wherein the source of the MSC is selected from the group consisting of bone marrow, adipose tissue, and umbilical cord. 
     
     
         11 . The composition of  claim 10 , wherein the umbilical cord MSC is harvested from human umbilical cord perivascular tissue. 
     
     
         12 . The composition of  claim 1 , wherein the therapeutic agent is a recombinant anti-tumor gene. 
     
     
         13 . The composition of  claim 1 , wherein the therapeutic agent is en oncolytic virus. 
     
     
         14 . The composition of  claim 13 , wherein the oncolytic virus is engineered to express a recombinant anti-tumor gene. 
     
     
         15 . The composition of  claim 12 , wherein the anti-tumor gene is selected from the group consisting of an interferon, an interleukin, a chemokine, a suicide gene, and any combination thereof. 
     
     
         16 . The composition of  claim 15 , wherein the anti-tumor acne is selected from the group consisting of interferon α, interferon β, interleukin 1, interleukin 12, CX3CL1, thymidine kinase, IL-12, IFN-gamma, TNF-alpha, and any combination thereof. 
     
     
         17 . The composition of  claim 1 , wherein the MSC further comprises a recombinant AMF receptor. 
     
     
         18 . The composition of  claim 1 , wherein the MSC stimulated with rAMF expresses increased levels of matrix metalloproteinase (MMP) after rAMF stimulation. 
     
     
         19 . The composition of  claim 18 , wherein the MMP is selected from the group consisting MMP2, MMP3, or any combination thereof. 
     
     
         20 . A method for increasing migration or anchorage of a mesenchymal stromal cell (MSC) to a tumor comprising (a) stimulating the MSC with a recombinant autocrine motility factor (rAMF), and (b) administering the stimulated MSC of (a) t the tumor, wherein the MSC comprises a therapeutic agent. 
     
     
         21 . A method for treating a subject with a tumor comprising (a) stimulating a mesenchymal stromal cell (MSC) comprising a therapeutic agent with a recombinant autocrine motility factor (rAMF), and (b) administering the stimulated MSC of (a) to the subject. 
     
     
         22 . The method of  claim 20 , wherein the tumor is a solid tumor. 
     
     
         23 . The method of  claim 20 , wherein the tumor is a cancer selected from the group consisting of a liver cancer, a colon cancer, a pancreatic cancer, a lung cancer, a gastrointestinal cancer, a kidney cancer, or a breast cancer. 
     
     
         24 . The method of  claim 20 , wherein the tumor is a carcinoma. 
     
     
         25 . The method of  claim 24 , wherein the carcinoma is hepatocellular carcinoma (HCC). 
     
     
         26 . The method of  claim 24 , wherein carcinoma is colorectal carcinoma. 
     
     
         27 . The method of  claim 20 , wherein the tumor expresses endogenous AMF. 
     
     
         28 . The method of  claim 20 , wherein the increased migration is two-fold greater than migration of the MSC without rAMF stimulation. 
     
     
         29 . The method of  claim 20 , wherein the source of the MSC is selected from the group consisting of bone marrow, adipose tissue, and umbilical cord. 
     
     
         30 . The method of  claim 29 , wherein the umbilical cord MSC is harvested from human umbilical cord perivascular tissue. 
     
     
         31 . The method of  claim 20 , wherein the therapeutic agent is a recombinant anti-tumor gene. 
     
     
         32 . The method of  claim 20 , wherein the therapeutic agent is an oncolytic virus. 
     
     
         33 . The method of  claim 32 , wherein the oncolytic virus is engineered to express a recombinant anti-tumor gene. 
     
     
         34 . The method of  claim 31 , wherein the anti-tumor gene is selected from the group consisting of an interferon, an interleukin, a chemokine, a suicide gene, and any combination thereof. 
     
     
         35 . The method of  claim 34 , wherein the anti-tumor gene is selected from the group consisting of interferon α, interferon β, interleukin 1, interleukin 12, CX3CL1, thymidine kinase, IL-12, IFN-gamma, TNF-alpha, or any combination thereof. 
     
     
         36 . The method of  claim 20 , wherein the MSC further comprises a recombinant AMF receptor. 
     
     
         37 . The method of  claim 20 , wherein the MSC stimulated with rAMF expresses increased levels of matrix metalloproteinase (MMP) after rAMF stimulation. 
     
     
         38 . The method of  claim 37 , wherein the MMP is selected from the group consisting MMP2, MMP3, or any combination thereof. 
     
     
         39 . The method of  claim 21 , wherein the administration is systemic. 
     
     
         40 . The method of  claim 21 , wherein the administration is to an intra-hepatic artery.