Advances in understanding of the molecular mechanisms involved in treatment response might open up new ways to select patients for particular treatments and to develop new treatment strategies. For example, radium, a bone-targeting alpha particle emitter, improves survival among men with metastatic castration resistant prostate cancer mCRPC. But the molecular basis for that benefit has remained a largely open question. Part of the answer to that question, it turns out, might be that prostate cancer cells frequently evolve to mimic bone tissue, which can facilitate the uptake of radium by bone-dwelling prostate tumor metastases, according to the authors of a study conducted at the Duke Cancer Institute in Durham, North Carolina, which was presented during the Symposium panel session.
The study included 20 patients with heavily pretreated and symptomatic bone mCRPC who were treated with radium for a median of 6 doses. The investigators identified circulating tumor cells CTCs in many patients with evidence of osteomimicry. Login Register. Nevertheless, the good tropism of retroviruses to the host cells formed the basis for developing the replication-defective retroviral vectors Despite an early reception of large attention to retroviral vectors, nowadays the clinical use of these vectors has been declined because many difficulties have been found to be associated with these vectors such as the absence of long-term transgene expression, ineffective transduction of MSCs, induction of insertional mutagenesis, and the requirements for administering high loads of vectors in several rounds to transduce host cells 66 Table 3.
Application of these vectors has been limited regarding their very low aptitude for MSCs transduction. Although an ultraviolet light-activated transduction system has been developed to increase the transduction efficiency of these vectors, but clinical applicability of AAV vectors still remained doubtful 65 , However, there are also some difficulties in finding a laboratory friendly way for the expansion and production of replication-defective yet with high transduction efficiency HVS-V.
These problems have prevented the extensive clinical use of these vectors 67 Table 3. Non-viral vectors such as plasmids have been utilized as another appropriate candidate for gene delivery into MSCs.
Traditional transfection methods e. The transfection methods usually lead to a high ratio of mortality Nonetheless, in a novel method developed by Song et al. The method has been characterized by some notable benefits such as the high transfection efficiency, low cell mortality and no interference with the normal activities of the cells Moreover, other options of transfection-mediating methods have been advanced in which each provides some strengths besides some weaknesses.
In this regard, an improved method has been introduced for constant transfection of MSCs with the help of electric power termed as the electroporation In the proposed method, MSCs were transfected with pDNA using the electroporation technique, which resulted in a high ratio of successful transfection and constant expression of the transgene.
Therefore, pDNAs can provide an easy transfection procedure while preserving the proper biological properties of the host cells A novel method for efficient transfection of MSCs has also been recently developed based on therapeutic ultrasound TUS. The stemness, surface markers and homing properties of MSCs remained intact. Briefly, it could be pointed out that in recent years an exceptional progress in the field of gene delivery modalities occurred by introducing the various innovative modified non-viral vectors with the purpose of effective and perfect gene delivery Table 3. Given the lack of a generally accepted method for safe usage of MSCs with minimal toxicity and harmful effects 5 , 6 , there is still crucial requirement in developing novel targeted therapy methods with high toxicity against tumor cells while maintaining their safety in touch with normal cells.
However, MSCs are the stem cells with high capacity of differentiation to various types of cells.
Since the high capability of differentiation, serious concerns have been raised about the possibility of converting MSCs to tumor cells, particularly under the impression of the tumor milieu 5. In addition, MSCs are relatively large cells and in the case of confronting the immune system, they can be readily detected and phagocytized by the immune cells 5. In accordance, MSCs can also be internalized by cannibal tumor cells which then direct the tumor cells to enter dormancy.
The dormancy of tumor cell is now thought to be one the major reasons responsible for a phenomenon called tumor relapse Furthermore, the deliverance of genetic material either by viral or non-viral vectors can increase the chance for induction of insertional mutations in MSCs or in accidentally targeted cells such as normal cells. Wrongly targeting the normal cells instead of tumor cells can end in loss of the proper functions of the cells or even conversion to the cancerous cells 5 , 6.
On the opposite side, a series of solutions have been raised regarding the mentioned concerns. This implies that intact MSCs itself can act as the drugs due to their internal capability of secretion of therapeutic anticancer agents 3. Thus, administration of intact and unmodified MSCs can be just enough therapeutic against simple non-extensive injuries or non-aggressive tumors at their primary stages 3. Additionally, a surprising characteristic of MSCs is recently discovered; ability to intake the drug particles without being damaged and subsequent gradual release of the drug within the tumor after migration to the tumor site s 6.
This property makes the MSCs needless to be genetically modified and deliver the exotic and possibly mutation-inducing vectors 6. In addition, MSCs can produce large amounts of the vesicles containing therapeutic agents with paracrine-like actions against tumor cells. Also, some promising novel genome editing tools have been developed recently. The methods are based on using the proteins that can recognize the specific sequence s on the genome. Generally, the protein is also accompanied by a nuclease to cut the recognized sequence. These systems provide accurate and sequenced-specific genome editing and can be practical in reliable delivery and integration of a therapeutic gene into the genetic material of MSCs without the risk of induction of undesired mutations 1.
Alternatively, a method based on making a decoy comprised of nano-sized membranes of MSCs containing the therapeutic drugs has been advanced recently. In this method, the anticancer agents are loaded into the surface marker-consisted membranes of MSCs. Then the membranes are homogenized into the nano-sized vesicles which are termed as nano-ghosts. The MSC-derived nano-ghosts have the advantage of completely being safe due to the inability to carry any genetic material. However, these nano-ghosts also inherit the superior property from their mother cells which is the specific tumor tropism Another vector-free method is based on loading the mRNAs into the stem cells instead of genetic modification with the advantage of bringing the probability of insertional mutation s to near zero.
This occurs because unlike the DNA-based methods which are done by the integration of exotic genetic material into the genome in nucleus, the mRNAs are needless to be sent into the nucleus and are translated directly within the cytoplasm into the therapeutic proteins.
However, the rapid degradation and instability of mRNA limit the broad use of this method Recently, an alternative method of indirect gene therapy using small nucleotide molecules interfering with or controlling the gene regulation was also proposed The shRNA can be delivered on a plasmid to host cell However, cell-based delivery systems such as MSCs can also be used to deliver these molecules to knock down an oncogenic gene as a cancer therapy. The viral vectors containing or inducing these molecules can also be employed directly for transfection of the tumor cells or within a cell vehicle e.
Additionally, a method was developed to induce anticancer action of transgene MSCs specifically within cancerous tissues not in other tissues which MSCs may also migrate into them. Additionally, the gene encoding the sodium iodide symporter NIS protein is employed as the theranostic gene. The MSCs carrying the NIS were injected to an animal model of metastatic colon cancer, and then a radioisotope of iodine was also injected to mouse models. The NIS protein mediates uptake of radioactive iodine into the tumor tissue which leads to subsequent sequestration of the tumor growth.
This method provides a tumor site-directed anticancer therapy without any side effects on normal tissues Same method was also successfully used for the treatment of xenografts of hepatocellular carcinoma HC in mouse. Linking the activation and expression of NIS to tumor stroma of HC resulted in tumor-specific therapeutic action and, therefore, significant inhibition of tumor growth Moreover, in the case of preventing the rejection by immune system, it was suggested to use autologous MSCs rather than allogeneic or heterologous MSCs.
However, another option to overcome the challenge of redundant immune responses against injected MSCs is a procedure so-called selective allo-depletion. The method is mediated through depletion of alloreactive T cells while preserving their activity against tumor cells 5. Furthermore, in order to overcome the cannibalization by tumor cells or internalization by immune cells, some methods based on the MSCs surface marker refinement or transduction with a cannibalism-suppressing gene, have been developed.
Also, to avoid being faced with malignant transformation s , researchers have suggested to use the BM-MSCs due to their good genetic stability but on the other hand the low anticancer or even tumorigenic effect of this type of MSC have limited their usage in cancer therapy.
Encouraging results by the use of MSCs as carriers of therapeutic genes in the treatment of a variety of tumors have paved the way for extensive clinical use of this method. Engineered MSCs can overcome many of the problems caused by systemic injection of cytokines and antitumor agents such as the high cytotoxicity and low half-life. However, there are also some pitfalls in the usage of MSCs which lead to a significant delay in the clinical application of the MSCs.
The main problem in cancer gene therapy is the lack of a suitable gene carrier and very low efficiency of transfection of therapeutic genes.
The low transfection efficiency generally ends in low expression of delivered gene. For gene delivery, the viral and non-viral vectors are used to arm host cells e. Additionally, there are also some hurdles holding back, however temporarily, conquering in frontline of therapy of cancer; for instance, the lack of a technically suitable vector with high transduction efficiency and safety while being non-immunogen. These deprivations warrant further precise examinations on the vector-based targeted cancer therapy using MSCs as gene carriers. Thus further studies should be done to predispose the MSCs for clinical use.
This can be achieved by standardization and improving the methods of MSCs isolation, culture conditions, gene transfer and the tumor tropism. Also, it is essential to determine the best source of MSCs for each disease, the number of cells, appropriate site of injection, and the best time for injection in the therapy of different types of cancers. All authors contributed to the conception and the main idea of the work.
FM and GV drafted the main text, figures, and tables. AB and AE supervised the work and provided the comments and additional scientific information. SA reviewed and revised the text. All authors read and approved the final version of the work to be published.
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