The CD34 molecule is a commonly targeted antigenic determinant used as a characteristic marker to isolate and analyze hematopoietic stem cells.1–9 This protein is expressed by all hematopoietic stem cells and its expression is lost during the cell differentiation. Therefore, mature hematopoietic cells are usually CD34 negative.1 On the other hand, this molecule is also present in a variety of mature cell types, as mesenchymal cells, muscle satellite cells, corneal keratocytes, interstitial cells, epithelial progenitors, vascular endothelial progenitors, and activated endothelial cells.10 Of note, CD34 expression has been already correlated to vasculogenic and angiogenic processes, the mesenchymal CD34+ stem cells being closely associated to vascularization.1,4–6,8,9,11 Importantly, both vasculogenic and angiogenic processes are essential to the development of cancer.12–17Additionally, there are numerous studies describing CD34 expression in tumor cells,2,5,6,9,18 although the loss of this molecule has been associated with an invasive malignant phenotype.8,19 In this context, the CD34 molecule can be viewed in neoplastic cells as a dedifferentiation marker. Also, CD34 could be expressed by endothelial cells and endothelial progenitors as a potential tumor vascularization marker.

Chemokines are fundamental regulators of the development, differentiation, and migration of leukocytes.20–24 In addition, chemokines participate in the angiogenic process.21,25 The CC Chemokine Receptor 5 (CCR5) is a well-known example of such molecules, being especially involved in leukocyte migration.26 Furthermore, CCR5 is well-known due to its classic role as a co-receptor molecule used by the HIV type I viruses.21,25,27–31 In addition, CCR5 acts in Th1 immune responses and the lack of signaling through this molecule leads to a shift in the Th2 responses.20,21 Several chemokines were described as efficient agonists of this receptor, such as RANTES (CCL5), MIP-1α (CCL3) and MIP-1β (CCL4). On the other hand, some chemokines interact less efficiently with CCR520–22,25,27,32 or are classified as CCR5 antagonists, which is the case of CCL7.25,29 Of note, the impact of CCR5 on the development of cancer is an emerging topic, with several studies suggesting that CCR5 plays an important role in the establishment of the tumor microenvironment and progression of different types of cancer. Notably, the CCR5 molecule has been related to the migration and spread of tumor cells, and therefore, to metastasis. Moreover, the presence of the receptor in neoplasms has been associated with the migration of regulatory cells and generation of an immunosuppressor tumor-prone environment. Detailed examples and other effects of CCR5 on tumorigenesis are shown in Table 1.22–24,33–44

As mentioned above, the CCR5 protein has a regulatory effect on inflammatory cells,26,27 thus it must have an enhancing function in the migration of pivotal cells for tumorigenesis, explaining at least partially its connections with the development of cancer. Importantly, the CCR5 expression was already observed in some regulatory T (Treg) cell subsets.45–50 In certain circumstances and types of cancer, Treg cells were linked with a better prognosis.51 Nevertheless, we are facing a two-edged sword, since Treg cells can also be subverted by tumor cells in order to generate a tolerogenic environment, allowing the proliferation and establishment of neoplasms.52–55 Thus, we can suppose that the absence of CCR5 in Treg cells may be a protective factor in the context of tumorigenesis.

The role of the immune system in the development of cancer is a field of extensive debate. Even though inflammatory cells could eliminate tumor cells, inducing their death, they are also important components of the tumor microenvironment, sometimes favoring tumor growth and proliferation, also promoting neoangiogenesis.36–38 In this sense, some immune cell-derived factors, when in disbalance, can promote tumor progression. Adding to the complexity of the interactions happening in the tumor, there is a wide variety of immune cells in a neoplastic environment, including lymphocytes, macrophages, neutrophils and dendritic cells, which can produce cytokines and other mediators that enhance the tumor development.56 The immune surveillance and the individual responses to cancer therapy are also affected by different inflammatory patterns.57

Recently, a study performed by Enrich et al.58 raised intriguing results. A cohort of Spanish cord blood donors was genotyped for the CCR5Δ32 polymorphism (rs333), a genetic variant which consists of a 32 base-pair deletion in the open reading frame of the CCR5 gene. This deletion causes a premature stop-codon, which leads to the formation of a truncated protein that is not expressed on the cell surface.30,31 Heterozygous and homozygous individuals for CCR5Δ32 show respectively reduced CCR5 expression and no expression of the CCR5 molecule on the cell surface.59,60 As previously mentioned, CCR5 is an HIV-I co-receptor and this genetic variant became widely known due to its association, when in homozygous, to resistance against HIV infection.61,62 The main objective of Enrich et al.58 was to identify the CCR5Δ32 homozygous cord blood units, which could be used as donor cells to be transplanted to HIV+individuals. The idea was that the CCR5Δ32 homozygous cord blood units would repopulate the host with a set of cells which would not allow HIV infection, avoiding the maintenance of the virus infection, eventually leading to viral clearance. A similar approach using bone marrow CCR5Δ32 homozygous cells has been successfully applied in one patient, who remains with sustained suppression of the HIV infection.63–65 Nevertheless, among the results of Enrich et al.,58 one was surprising and unprecedented: a smaller amount of CD34+ cells was found in the samples from the CCR5Δ32 homozygous donors, as compared to both heterozygous and CCR5 wild-type homozygous. This situation represents a drawback to the main objective of the authors since a) fewer cells would be available from these donors and b) potentially cord blood units from those CCR5Δ32 homozygous donors would present a lower reconstitution potential of the host leukocyte repertoires. In this same study,58 Enrich et al. suggested that CCR5 and its agonist MIP-1α (CCL3) play a critical role in the hematopoietic stem cell function. Specifically, MIP-1α possibly regulates cytokine-induced stem-cell proliferation and the lack of CCR5 in Δ32/Δ32 individuals might disrupt the MIP-1α signaling pathway and explain the lower CD34+ cell counts.20,58,66–68 From this unexpected result, a new point emerged: a connection between CCR5 and CD34+ cells.