By utilising the techniques of bibliometric analysis, it is possible to access a large repository of publications and make certain judgements regarding the field of interest based on bibliometric parameters. The unique strength of bibliometric analysis over a traditional literature review is that the analysis facilitates the input of a far greater number of articles, which in turn constitutes more meaningful recommendations to researchers. From the outset of this paper, the aim of the authors was to make a commentary on the current state of the field of MSCs in cancer research and provide insights into which research streams are worthy of attention in the future.
Our analysis has included almost 10,000 publications from which the field of MSCs in oncology has been assessed and the publication data shows considerable growth within the field over the past 20 years, peaking in 2017. Less publications in 2018 however, does not preclude the possibility that the field is still undergoing continued growth. It has been noted previously that delayed indexing of published articles on the WoS platform can result in an underrepresentation of the publication statistics for more recent years (20). Another reason for the drop in 2018 can be attributed to the natural progression of the field commonly seen in bibliometric analyses. As research fields become more mature and publications of a rudimentary nature saturate the field, research naturally shifts towards more novel niches of investigation. Turning points such as this have been documented in numerous fields of study previously (29, 30). When considering the publications from 2018, one must also make a note of nomenclature. Mesenchymal Stromal Cells are closely related to the alternatively named Cancer Associated Fibroblasts (CAFs), both of which are fibroblastic cells that support cancer proliferation, survival, chemoresistance and immune-evasion in the TME (31). An increase in the use of the “CAF” terminology may also have contributed to the number of MSC publications in 2018.
Development of research fields is said to follow four stages; initially only a small number of contributors publish on a topic until the field receives wider acceptance and enjoys exponential growth. Upon saturation of the field, publications plateau at maturity until an ultimate decline in publications (32, 33). Based on the data we have presented and the strong R2 value of 0.97, the field of MSCs in cancer research are currently undergoing the exponential phase of growth similar to that seen in other fields of study (33). This identified trend in the field of MSCs in cancer research is encouraging news for prospective cell biologists and cancer researchers with an interest in the TME, as it indicates a continued appetite for this type of research among the scientific community.
The citation data also aligns itself with the aforementioned 4 phases of research field maturity. In the early phases, the small number of publications were highly cited as interest in the field grew, resulting in more publications. The consequence of this high output however corresponded with an exponential decrease in the number of citations per item, the inverse of publication volume. While this citation bias is understandable as the field matures, researchers need to have an awareness of such phenomena when considering the merit of prior research and should also seek out the high citation articles that provided the foundation for the field’s subsequent exponential growth.
Geographically, this field receives contribution from many jurisdictions, with over 90 countries contributing. The United States and the Peoples’ Republic of China account for a significant volume. Both of these countries have been identified previously as power houses for publishing research in the field of cancer and others (34–38). Despite their high overall output, correction for population has highlighted research hotspots such as Luxembourg, Switzerland and Singapore who lead the world in publications per capita but also have the highest average citations among all countries. In considering collaborative working, these findings can inform researchers within this field of study. Particularly, when collaborations are sought within Europe, the impressive performances of Luxembourg and Switzerland make institutions from those countries worthy of research partnerships.
In relation to the journals that publish most prolifically, there is a mix of dedicated cell biology journals such as “Stem Cells” but also those with a broader cancer research focus such as “Oncotarget”. Over time, publications on MSCs in oncology were increasingly seen in journals with a deliberate cancer focus (Fig. 3B), this suggests that while publications were originally in journals dedicated to studying cells eg. “Stem Cells”, future research will be most appropriately published in cancer journals. This finding is a positive development as it demonstrates a wider acceptance of MSC research in the cancer community rather than exclusively the interest of cell biologists.
As a field matures, it is expected that publications will shift from preclinical to translational and ultimately clinical. This process has been studied in detail by Weber et al. who describe the challenge of accurately determining what stage a field is at by bibliometric analysis (39). In our attempt to make this determination about MSCs in cancer research we have taken a similar approach to Narin et al, whereby publishing journals were designated as either basic, translational or clinical and their publication data was subsequently analysed over time (40) (Fig. 3C). Our findings demonstrate strong predominance of basic science/preclinical research which increased over a 15 year period. One may expect that basic science research would decrease overtime while translational and clinical publications increased. At this point that is not the case and there seems to be a continued appetite for bench research on MSCs in cancer. In the interest of developing future projects this indicates that while, basic science studies are still in demand, the aspiring cancer researcher who incorporates translational or clinical components will fill a relatively unmet need within the literature.
Of the cancers analysed, studies on breast cancer were most frequently published. The proportion of publications relating to breast cancer exceeded both its incidence and rate of mortality relative to the other cancers examined. This finding is not particularly novel as other bibliometric analyses indicate that breast cancer predominates various cancer research fields (41, 42) and also enjoys considerable funding (43). For those embarking on research involving MSCs in oncology, the implications of this finding are twofold. Firstly, institutions publishing on breast cancer have an established process and a strong track record of published outputs, making them promising collaborators. Secondly, given the near saturation of publications relating to breast cancer, the lesser studied cancers may contain novel findings that remain uncovered.
The keyword analysis (Fig. 5A&B) provides an insight into the content of published articles relating to MSCs in cancer research. There are a number of familiar keywords among the more prevalent in the literature, for example “Mesenchymal Stem Cell” and “emt”. Epithelial to Mesenchymal Transition (emt) has long been identified as a mechanism by which MSCs support tumour progression and cancer cell survival within the TME (44). Furthermore, EMT has previously been identified as a research hotspot in cancer research, by bibliometric analysis (45). While its frequency within the literature supports its importance in MSC research and the expertise that exists within the scientific community, the search for novelty is likely to be found elsewhere within the cluster analysis. The cluster relating to clinical research (Fig. 5A blue), is noticeably underdeveloped compared to the other two. Prominent keywords such as “case”, “concept” and “review” suggest that original, applied MSC research in this area is underrepresented. Consistent with the underdevelopment of translational research, this cluster demonstrates a need for future research on MSCs in oncology that has a translational or clinical component. The cluster analysis also demonstrates the change in keyword prevalence over time within the literature (Fig. 5B). The older terms along this spectrum include “Mesenchymal Stem Cell”, “Media”, “Osteoblast” and “Bone Marrow” and are almost exclusively situated within the cluster relating to the identification and characterisation of these cells. This is not peculiar as earlier research will be expected to focus on identification of MSCs in tumours and determining their characteristics. Conversely, the more current keywords include the aforementioned “emt” along with “microRNA”, “Metastasis” and “e cadherin” all of which reside within the cluster pertaining to molecular function (Fig. 5A green). The temporal shift towards MSC function in the TME alongside our other data certainly suggest that future directions in the field will be on the functional elements of MSCs and how these can be manipulated to clinical and therapeutic advantage.