Upsala Journal of Medical Sciences ISSN: 0300-9734 (Print) 2000-1967 (Online) Journal homepage: https://www.tandfonline.com/loi/iups20 Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors Annika Jögi, Marica Vaapil, Martin Johansson & Sven Påhlman To cite this article: Annika Jögi, Marica Vaapil, Martin Johansson & Sven Påhlman (2012) Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors, Upsala Journal of Medical Sciences, 117:2, 217-224, DOI: 10.3109/03009734.2012.659294 To link to this article: https://doi.org/10.3109/03009734.2012.659294 © Informa Healthcare Published online: 29 Feb 2012. Submit your article to this journal Article views: 1341 View related articles Citing articles: 63 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iups20 Upsala Journal of Medical Sciences. 2012; 117: 217–224 REVIEW ARTICLE Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors ANNIKA JÖGI1,2, MARICA VAAPIL1,2, MARTIN JOHANSSON1 & SVEN PÅHLMAN1,2 1Department of Laboratory Medicine, Center for Molecular Pathology, Skåne University Hospital Malmö, Malmö, Sweden, and 2CREATE Health, Lund University, Malmö, Sweden Abstract The differentiation stage of tumors is a central aspect in the histopathological classification of solid malignancies. The differentiation stage is strongly associated with tumor behavior, and generally an immature tumor is more aggressive than the more differentiated counterpart. While this is common knowledge in surgical pathology, the contribution of differentiation-related gene expression and functions to tumor behavior is often overlooked in the experimental, tumor biological setting. The mechanisms by which tumor cell differentiation stages are perturbed or affected are poorly explored but have recently come into focus with the introduction.of the tumor stem cell concept. While developmental biologists view the differentiation as a unidirectional event, pathologists and tumor biologists have introduced the concept of dedifferentiation to explain phenotypic changes occurring in solid tumors. In this review we discuss the impact of the tumor cell differentiation stage as used in surgical pathology. We further discuss knowledge gained from exploring the molecular basis of the differentiation and dedifferentiation processes in neuroblastoma and breast cancer, two tumor forms where the tumor cell differentiation concept is used in the clinical diagnostic work and where the tumor stem cell theory has been applied. Key words: Breast cancer, dedifferentiation, differentiation, EMT, hypoxia, neuroblastoma, prostate cancer, skin cancer, tumor-initiating cells, tumor stem cells Introduction differentiation processes, but rather studied molecular pathways leading to growth, migration, and cell death. The biological meaning of the term differentiation However, the rapid and recent development of stem denotes the developmental process whereby cells grad- cell as well as tumor stem cell research have galvanized ually acquire the capacity for a more specialized func- the study of the differentiation processes in cancer, tion by change of phenotype. While developmental which has provided insights into the cellular and biologists generally view this process as unidirectional, molecular biological underpinnings of cancer-driven observations in the context of cancer show that the mechanisms leading to changes in the degree of cellular differentiation process can reverse and that cells can differentiation or dedifferentiation. In this contribution dedifferentiate. Despite the fact that classical tumor we discuss the impact of the tumor cell differentiation diagnostics based on surgical pathology and histology stage on tumor behavior and the use of this important for decades have used tumor cell differentiation status concept in surgical pathology. We further summarize as one important aspect to score, evaluate, and com- knowledge gained from exploring the differentiation municate tumor aggressiveness, overall experimental and dedifferentiation processes in two tumor forms, tumor biology has over the years not focused on the neuroblastoma and breast cancer. Correspondence: Sven Påhlman, Center for Molecular Pathology, Department of Laboratory Medicine, Skåne University Hospital Malmö, Entrance 78, S-20502 Malmö, Sweden. Fax: +46 40336073. E-mail: [email protected] (Received 13 October 2011; accepted 17 January 2012) ISSN 0300-9734 print/ISSN 2000-1967 online Ó 2012 Informa Healthcare DOI: 10.3109/03009734.2012.659294 218 A. Jögi et al. Differentiation as a prognostic parameter in growing as separate units in the prostatic tissue, still surgical pathology respecting other glands, malignant as well as benign. Grade 4 heralds that the malignant glands start to In the realm of surgical pathology, the concept of coalesce and fuse, whereas grade 5 show malignant cellular differentiation is made very concrete although cells growing either in sheets or as single cell units, used from a different angle and with a somewhat totally devoid of gland-forming capacity. To arrive at different content than its usage in developmental the Gleason score, the grade of the most commonly biology. Apart from performing the obvious task of seen cancer (e.g. 3) is added to that of the minority ruling out/determining whether a tumor is malignant pattern (e.g. 4), which gives a Gleason score of 7. In or benign, the pathologist also most often evaluates this case a composite score based on the degree of malignancies aiming to assess their degree of differ- dedifferentiation is used, which has contributed sig- entiation, implying that neoplastic cells have the nificantly to the prognostic power of the Gleason potential to slide back along the line of differentiation. grading system. The result has prognostic implications where, as a The morphological correlates of dedifferentiation rule, a high degree of differentiation purports a better have been known to pathologists for over a century, prognosis than a low degree. Using morphological but an explanation of the mechanistic factors behind criteria, the degree of resemblance between the neo- this process has been lacking and unexplored until plasia and its tissue of origin is gauged. A high degree recent times when the armamentarium of cellular of differentiation means that the neoplasia is morpho- and molecular tumor biology has been deployed to logically similar to the native organ, forming neoplas- study this phenomenon. A process of interest in this tic organoid structures, whereas the opposite is true context is the epithelial to mesenchymal transition for a low stage of differentiation, where cells gradually (EMT). This term describes how epithelial cells lose the capacity for structural organization and start phenotypically transdifferentiate towards a more mes- to display reduced cohesiveness and where the term enchymal/fibroblastoid/spindle-shaped cell, simulta- anaplasia denotes tumor morphology where all sim- neously gaining increased capacity for invasiveness ilarity with the origin has been lost. and motility. An important question in this context is The results from evaluating the degree of differ- to what degree EMT equates to dedifferentiation. entiation are often presented using a two- or three- Addressing this issue, it is important to remember tiered scale as exemplified by the common skin that, by definition, carcinomas develop from epithelial malignancy, squamous cell carcinoma (SCC). If a cells. Epithelial cells, however, are not defined at a case of SCC grows in an outward (verrucous) fash- cellular but at an architectural level, where epithelial ion, still maintains keratin-forming capacity, has cells form multidimensional cohesive cellular sheets cells with ample cytoplasm, only slight nuclear aty- of varying thickness resting upon the basal lamina, pia, and only few mitotic figures, it is regarded as resulting functionally in immobile cells. The mesen- highly differentiated. This means that no signs of chymal cell, on the other hand, is defined at a cellular invasion below the basal membrane are seen and level, being spindle-shaped, bipolar, and motile. metastatic disease is rare. On the other side of the These cellular categories are the two prototypic cells scale is the SCC of low differentiation, where cells of chordates (1) from embryogenesis and onwards. grow in sheets and with no signs of keratin formation. Actually, the co-ordinated actions of these dual cell In these cases the mitotic index is often high, and types form the very basis for development of occasionally immunohistochemistry has to be used higher life forms, above the level of amphioxi, under- to conclude that this cancer indeed is derived from scoring their fundamental developmental importance. the squamous epithelium. Biologically, these poorly With this definition in mind the terms dedifferentia- differentiated cancers often invade deeply through tion and EMT show a considerable degree of con- the dermis and have a bad prognosis with a propen- ceptual overlap. Although implicated during invasion, sity for lymph node metastasis. In between these intravasation, and metastasis, clear-cut examples of poles are the intermediately differentiated cases of clinically relevant EMT in cancers have been hard to SCC. demonstrate, even if attempts have been made (2). Another pertinent example of how differentiation However, as pointed out, dedifferentiated