Stem Cell Therapy: Potential Treatment for Cancer Cure Bhatt K, Bhogle P VES Collegeof Pharmacy,Chembur

Introduction• Conventional chemotherapy treatments along with killing of tumour cells, kills

chunk of healthy cells leading to myelosuppression and still occurrence of relapse. • Where the conventional therapies fail, “STEM CELL THERAPY” may serve as

1.immuno-reconstituents2.vehicle in targeted delivery of chemotherapeutic agents 3. Kill the tumour cells by inducing genetic changes especially the cancer stem

cells which have tumour initiating potential and are responsible for the growth of the tumour and metastasis.

• Aim of this review is to primarily focus on the recent developments in the use of the stem cells in the cancer treatments, then to discuss the cancer stem cells, now considered as backbone in the development of the cancer; and their role in carcinogenesis and their implications in the development of possible new cancer treatment options in future.

What are Cancer Stem Cells?

• Cancer stem cells can be defined as cells in the tumour growth with a tumour initiating potential. They survive much longer than ordinary cells thus increasing the chance that they might accumulate genetic mutations. It might take only a few mutations for one cell to lose control over its self-renewal and growth and become the source of cancer.

• Normal stem cells or progenitor cells

development of the primary tumour.

• During chemotherapy, most of the primary tumour cells may be destroyed but if cancer stem cells are not eradicated, they become refractory cancer stem cells and may lead to recurrence of tumour, the cancer stem cells may emigrate to distal sites from the primary tumour and cause metastasis.

• Cancer stem cells are more resistant to chemo- and radiotherapy than other cells in a tumour. This could be one cause of tumour relapse after therapy.

cancer stem cellsmutation

Identification of Stem Cells

Cancer Stem Cells Tumour Cells

1.unlimited proliferative capability2.more quiescent3.no hyperproliferation signal liketyrosine kinase

1.limited proliferative capability2.less quiescent3.hyperproliferation signal liketyrosine kinase

• One approach to target the cancer stem cells may be the identification of the markers that are specific for the cancer stem cells compared to normal stem cells

1. haematopoietic stem cells express Thy-1 and c-kit whereas leukaemic stem cells express IL-3 (interleukin-3) receptor a-chain.

2. CD90 is Identified as a Candidate Marker for Cancer Stem Cells in Primary High-Grade Gliomas.

• There have been identification of cell-surface markers in the lung, brain and prostate which may allow the separation of the stem orprogenitor cells with the tumour initiating function.

• Stem cells from haemopoietic tissues have 'extraordinary' abilities to generate or switch between haematopoietic and non-haematopoieticlineages, exhibiting an unexpected degree of developmental or differentiation potential.

• The stromal stem cells derived from bone marrow have been used in the cell-based bone reconstruction following chemotherapy and surgery in osteosarcoma.

• Chemotherapy is followed by Stem Cell Therapy in many instances of leukemia, sarcomas and lymphomas to replenish the lost immunity of the patient and thus prolonging their life.

Stem Cell in Tissue Regeneration

• Cancer Stem cells send out chemo-attractants such as the vascular endothelial growth factor (VEGF) to recruit the transplanted stem cells to form the supporting stroma of the tumour, and pericytes for angiogenesis.

1. infiltrate metastatic tumor sites2. activate a chemotherapeutic drug, thereby localizing the drug's effects to the tumor

cells.• Thus stem cells may serve as a platform for delivery of biological agents in

tumors.

Stem Cell as a Delivery Vehicle

Stem Cell+pro-drug

Cytosine DeaminasePro-drug Drug

Tumor inhibited

– Stem cells could be genetically manipulated to introduce the therapeutic gene which may either be active or awaiting later activation.

– Tumor tracking properties of MSC provide an attractive opportunity for targeted transgene delivery into the sites of tumor formation.

– Human mesenchymal stem cells were isolated and transfected or transduced with a retroviral vector encoding a proapoptoticligand that induces apoptosis in a variety of human cancers but not normal tissues.

– Gene introduction into human mesenchymal stem cells could produce a tumor-specific prodrug converting cellular vehicle for targeted chemotherapy.

– Stem cells may be induced with the chemotherapeutic gene of the natural agents like vinca alkaloids and then transplanted in the tumour which reported not only kills the tumour cells but also avoid its relapse.

Stem Cell Mediated Gene Therapy

Advantages

1. As immuno-reconstituent following chemotherapy and radiotherapy.

2. localized therapeutic effect- Acts as targeted delivery vehicle into the tumour sites without affecting the neighbouring normal cells

3. Capable of killing even the cancer stem cells by genetically inducing changes in transplanted cancer stem cells.

4. Tissue regeneration

5. minimizing toxic side effects such as nausea, diarrhea or bone marrow suppression.

6. thrombocytopenia and neutropenia may be reduced post chemotherapy

Disadvantages

1. Some of the chemotherapeutic agents like alkaylating agents, should be avoided as they are reported to adversely affect stem cell yield and haematopoietic recovery.

2. Life span of bone marrow and adipose tissue derived stem cells is much less than that of embryonic stem cells so they have to be telomerised.

3. Cost Factor a bit on higher side

4. Therapy is being investigated on a lab scale so will take time to come into actual practice.

Conclusion

References1.Piera Dalerba,Robert Cho,Michael Clarke,Cancer Stem Cells:Models and Concepts,Stanford Institute for Stem Biology,Annu. Rev.Med.2007,58:267-842.K Nakamura,Y Ito,K Kuruzomil,Antitumor effect of genetically engineered mesenchymal stem cells in rat glioma model,Sapporo Medical University,Japan,Gene Therapy(2004)11,1155-11643.Giulia Grisendil,Rita Bussolari,Luigi Cafarelli,Adipose Tissue Derived Mesenchymal Stem Cells as source for Tumour Necrosis Factor Related Apoptosis Inducing Ligand,TUmour and Stem Cell Biology