br Implications for therapeutic intervention br Virtually
4.3. Implications for therapeutic intervention
Virtually every cervical cancer is the result of a human papilloma-virus infection. HPV transforms LDN 193189 in part by blocking tumor sup-pressors (p53 and RB) and by activating the catalytic subunit of telo-merase. HPV E6 and E7 also have a well-documented ability to disrupt DNA damage repair (Bristol et al., 2017; Moody, 2018; Spriggs and Laimins, 2017b). HPV transformed cells require continued expression of HPV oncogenes. Since HPV E6 and E7 hinder a cell's ability to protect itself from DNA crosslinks, every cell in HPV-associated tumors are predicted to share this defect. This could explain the eﬃcacy of cross-linking agents like cisplatin in the treatment of malignancies caused by HPV. Therapeutics could be better designed to target HPV-associated cancers if a greater understanding of the mechanisms by which HPV oncogenes induce sensitivity to DNA crosslinks is gained. We show that it is possible to acquire resistance to one source of DNA crosslinks while remaining sensitive to crosslinks from other origins, suggesting that tumors that have acquired resistance to cisplatin could remain sensitive to other crosslinking drugs such as chlorambucil or mitomycin c.
Finally, the importance of measuring the eﬀects of sub-erythemal doses of UV should be noted for studies addressing most clinically re-levant questions, particularly those relevant to sensitivity or tumor-igenicity. While exposure to high doses of UV or other crosslinking agents may provide interesting molecular insights, they likely induce diﬀerent repair responses than the levels seen in common exposure to UV or after chemotherapy (Quinet et al., 2016). Further, excessive damage is more likely to induce an apoptotic response rather than a full-fledged eﬀort to repair lesions.
Declaration of interest statement
The authors declare they have no conflicts of interest relevant to this manuscript.
CA160224 (NAW) and made possible through generous support from the Les Clow family (NAW) and the Johnson Cancer Research Center at Kansas State University (NAW). Additional support came from the Kansas INBRE in the form of a fellowship to SOW (K-INBRE P20 GM103418).
Productive replication of human papillomavirus 31 requires DNA repair factor Nbs1.
cervical cancer: future directions involving targeted agents. Crit. Rev. Oncol.
Mehta, K., Laimins, L., 2018. Human papillomaviruses preferentially recruit DNA repair factors to viral genomes for rapid repair and amplification. MBio 9, e00064-18.
Schärer, O.D., 2013. Nucleotide excision repair in eukaryotes. Cold Spring Harb. Perspect.
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Cervical cancer cells produce TGF-β1 through the CD73-adenosine pathway T and maintain CD73 expression through the autocrine activity of TGF-β1
Rosario García-Rochaa,b, Alberto Monroy-Garcíaa,c, Jorge Hernández-Montesa, Benny Weiss-Steidera, Vianey Gutiérrez-Serranoa,c, María del Carmen Fuentes-Castañedac, Luis Roberto Ávila-Ibarraa,c,d, Christian Azucena Don-Lópeza, Daniela Berenice Torres-Pinedac,d, María de Lourdes Mora-Garcíaa, a Laboratorio de Inmunobiología, UIDCC-UMIEZ, FES-Zaragoza, UNAM, Ciudad de México, Mexico b Programa de Beca Posdoctoral UNAM DGAPA-PAPIIT, Mexico c Laboratorio de Inmunología y Cáncer, UIMEO, H Oncología, CMN SXXI, Instituto Mexicano del Seguro Social, Ciudad de México, Mexico d Programa de Posgrado en Ciencias Biológicas, UNAM, Ciudad de México, Mexico
In cancer, the adenosinergic pathway participates in the generation of an immunosuppressive microenvironment and in the promotion of tumor growth through the generation of adenosine (Ado). The present study analyzed the participation of Ado, generated through the functional activity of the cervical cancer (CeCa) pathway in CeCa cells, to induce the expression and secretion of TGF-β1, as well as the participation of this factor to maintain CD73 expression. Ado concentrations greater than 10 μM were necessary to induce an increase of over 50% in the production and expression of TGF-β1 in CeCa tumor cells. Blockade of A2AR and A2BR with the specific antagonists, ZM241385 and MRS1754, respectively, strongly reversed the production of TGF-β1. TGF-β1 pro-duced by CeCa cells was necessary to maintain CD73 expression because the addition of anti-TGF-β neutralizing antibodies or the inhibition of TGF-βRI strongly reversed the expression of CD73 in the CeCa cells. These results suggested a feedback loop in CeCa cells that favors immunosuppressive activity through the production of TGF-β1 and Ado as well as the autocrine activity of TGF–β1 and expression of CD73.