bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒09‒27
three papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Biochim Biophys Acta Rev Cancer. 2020 Sep 19. pii: S0304-419X(20)30146-3. [Epub ahead of print] 188427
    Kes MMG, Van den Bossche J, Griffioen AW, Huijbers EJM.
      Macrophages are innate phagocytic leukocytes that are highly present in solid tumors, where they are referred to as tumor-associated macrophages (TAMs). In solid tumors, the microenvironment is often immunosuppressive and hypoxic regions are prevalent. These hypoxic conditions impose tumor cells to reprogram their metabolism, shifting from oxidative phosphorylation to anaerobic glycolysis. This so-called glycolytic switch enables hypoxic tumor cells to survive, proliferate, and eventually to outcompete untransformed cells. The hypoxia-induced change in tumor cell metabolism leads to the production of oncometabolites, among which are the glycolytic end-metabolite lactate and the tricarboxylic acid cycle intermediate succinate. TAMs can react to these oncometabolites, resulting in an altered maturation and the adoption of pro-angiogenic features. These angiogenesis-promoting TAMs have been reported to cooperate with tumor cells in the formation of new vessels, and even have been considered an important cause of resistance against anti-angiogenic therapies. For a long time, the mechanisms by which lactate and succinate activated pro-angiogenic TAMs were not understood. Researchers now start to unravel and understand some of the underlying mechanisms. Here, the importance of microenvironmental cues in inducing different macrophage activation states is discussed, as well as the role of hypoxia in the recruitment and activation of pro-angiogenic macrophages. In addition, the latest findings on the oncometabolites lactate and succinate in the activation of angiogenesis supporting macrophages are reviewed. Finally, various oncometabolite-targeting therapeutic strategies are proposed that could improve the response to anti-angiogenic therapies. SIGNIFICANCE STATEMENT: Tumor-associated macrophages (TAMs) are known promotors of tumor neovascularization, and significantly contribute to the emergence of resistance to anti-angiogenic therapies. Recent evidence suggests that the angiogenesis promoting phenotype of TAMs can be activated by hypoxic tumor cell-derived oncometabolites, including lactate and succinate. Here, the latest findings into the lactate- and succinate-mediated mechanistic activation of pro-angiogenic TAMs are reviewed, and therapeutic strategies that interfere with this mechanism and may delay or even prevent acquired resistance to anti-angiogenic agents are discussed.
    Keywords:  Angiogenesis; Cancer; Lactate; Macrophages; Oncometabolite; Succinate; TAM; Tumor; Tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.bbcan.2020.188427
  2. Biomedicines. 2020 Sep 20. pii: E365. [Epub ahead of print]8(9):
    Moog P, Schams R, Schneidinger A, Schilling AF, Machens HG, Hadjipanayi E, Dornseifer U.
      Hypoxia Preconditioned Plasma (HPP) and Serum (HPS) are two blood-derived autologous growth factor compositions that are being clinically employed as tools for promoting tissue regeneration, and have been extensively examined for their angiogenic activity. As yet, their ability to stimulate/support lymphangiogenesis remains unknown, although this is an important but often-neglected process in wound healing and tissue repair. Here we set out to characterize the potential of hypoxia preconditioned secretomes as promoters of angiogenic and lymphangiogenic sprouting in vitro. We first analysed HPP/HPS in terms of pro- (VEGF-C) and anti- (TSP-1, PF-4) angiogenic/lymphangiogenic growth factor concentration, before testing their ability to stimulate microvessel sprouting in the mouse aortic ring assay and lymphatic sprouting in the thoracic duct ring assay. The origin of lymphatic structures was validated with lymph-specific immunohistochemical staining (Anti-LYVE-1) and lymphatic vessel-associated protein (polydom) quantification in culture supernatants. HPP/HPS induced greater angiogenic and lymphatic sprouting compared to non-hypoxia preconditioned samples (normal plasma/serum), a response that was compatible with their higher VEGF-C concentration. These findings demonstrate that hypoxia preconditioned blood-derived secretomes have the ability to not only support sprouting angiogenesis, but also lymphangiogenesis, which underlines their multimodal regenerative potential.
    Keywords:  adipose-derived cell supension; adipose-derived stem cells; angiogenesis; blood-derived therapy; hypoxia; hypoxia preconditioned plasma; hypoxia preconditioned serum; lymphangiogenesis; lymphatic regeneration; peripheral blood cells
    DOI:  https://doi.org/10.3390/biomedicines8090365
  3. Oncol Lett. 2020 Nov;20(5): 229
    Wilhelm C, Scherzad A, Bregenzer M, Meyer T, Gehrke T, Kleinsasser N, Hagen R, Hackenberg S.
      Mesenchymal stem cells (MSCs) exhibit strong tropism towards tumor tissue. While MSCs generally surround tumors, they can also infiltrate tumors and thereby influence their proliferation. Interactions between MSCs and tumor cells are usually tested under normoxia, but the majority of solid tumors, including head and neck squamous cell carcinoma (HNSCC), are also characterized by hypoxic areas. Hence, the present study aimed to assess the interaction between MSCs and tumor cells under hypoxic conditions. MSCs were cultivated under normoxia and hypoxia, and conditioned media were used to cultivate the HNSCC cell line FaDu. The cell cycle distribution and viability of MSCs and the proliferation of FaDu cells were analyzed under normoxia and hypoxia, and changes in cytokine levels in the conditioned media were evaluated. No cell cycle changes were observed for MSCs after 24 h of cultivation under hypoxia, but the cell viability had declined. Hypoxia also led to a decrease in the proliferation of FaDu cells; however, FaDu cells proliferated faster after 48 h under hypoxia compared with normoxic conditions. This effect was reversed after incubation under normoxia for 72 h and hypoxia for 72 h. While these changes constituted a trend, these differences were not statistically significant. A cytokine assay showed an increase in interleukin (IL)-6 in the hypoxic medium. Overall, the results indicated that there was an interaction between MSCs and tumor cells. The presence or absence of oxygen seemed to influence the functionality of MSCs and their protumorigenic properties, in which IL-6 was identified as a potential mediator. Since MSCs are a component of the tumor stroma, further in vitro and in vivo studies are needed to investigate this interaction in order to develop novel approaches for tumor therapy.
    Keywords:  FaDu; cell cycle; head and neck squamous cell carcinoma; hypoxia; interleukin-6; mesenchymal stem cells; normoxia; proliferation
    DOI:  https://doi.org/10.3892/ol.2020.12092