Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jun 9:11:426.
doi: 10.3389/fgene.2020.00426. eCollection 2020.

Chemotherapy Curability in Leukemia, Lymphoma, Germ Cell Tumors and Gestational Malignancies: A Reflection of the Unique Physiology of Their Cells of Origin

Affiliations

Chemotherapy Curability in Leukemia, Lymphoma, Germ Cell Tumors and Gestational Malignancies: A Reflection of the Unique Physiology of Their Cells of Origin

Philip Savage. Front Genet. .

Abstract

Cytotoxic DNA damaging chemotherapy brings clinical benefits in the treatment of many metastatic malignancies. However routine curative treatment remains restricted to a small number of malignancies including acute leukemia, high grade lymphoma, germ cell tumors, gestational malignancies and some of the rare childhood cancers. The detailed explanation for this dramatic divergence in outcomes remains to be elucidated. However, we have previously argued that there is a strong correlation between presence of the unique genetic events of immunoglobulin gene variable/diversity/joining (VDJ) recombination, somatic hypermutation (SHM), meiosis, nuclear fusion and gastrulation occurring in cells of origin of these malignancies and their high sensitivity to DNA damaging chemotherapy. In this study we have reviewed some of the basic physiological information relating to the specialized activity and sensitivity to DNA damage mediated apoptosis of normal cells undergoing these processes. In each of unique genetic events there are dramatic changes in apoptotic sensitivity. In VDJ recombination and somatic hypermutation over 95% of the cells involved undergo apoptosis, whilst in meiosis and nuclear fusion there are dramatic short term increases in the apoptotic sensitivity to DNA damage. It is apparent that each of the malignancies arising during these processes retains some of the unique phenotype associated with it. The impact of the physiological differences is most clearly seen in the two non-mutational malignancies. Gestational choriocarcinoma which arises shortly after nuclear fusion is routinely curable with chemotherapy whilst CIMP-positive ependymomas which is not linked to any of the unique genetic events is highly resistant. A similar pattern is found in a pair of malignancies driven by a single driver mutation. Infantile acute lymphoblastic leukemia (ALL) arises in a cell undergoing the early stages of VDJ recombination and has a 40% cure rate in contrast pediatric rhabdoid malignancy which is not linked to a unique genetic event responds very poorly to chemotherapy treatment. The physiological changes occurring in cancer cells at the time of the malignant transformation appear to have a major impact on the subsequent sensitivity to chemotherapy and curability. New therapies that impact on these pathways may be of therapeutic value.

Keywords: apoptosis; cancer; chemotherapy; cure; phenotype.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Schematic summary of the hypothesis indicating the unique genetic processes, which are associated with dramatic changes in apoptotic sensitivity. These occur in the cancer cells of origin and a remnant of this activity persists in their subsequent malignant cells. This ongoing phenotype leads to a heightened apoptotic response to DNA damaging chemotherapy.
FIGURE 2
FIGURE 2
Sensitivity of colony forming units (CFU), pre-B cells and mature splenic B cells to cytotoxic chemotherapy drugs and radiation. ID50 is the drug concentration required to kill 50% of cells. D37 is the radiation dose (Gy) required to kill 37% of cells. It is apparent that Pre B cells are significantly more sensitive to DNA damaging agents than CFU or splenic B cells.
FIGURE 3
FIGURE 3
Sensitivity of embryonic cells to low dose radiation (0.5 Gy) before, during and after gastrulation. Data and graph taken from Heyer et al. (2000).

Similar articles

Cited by

References

    1. Abellar R. G., Pepperell J. R., Greco D., Gundogan F., Kostadinov S., Schwartz J., et al. (2009). Effects of chemotherapy during pregnancy on the placenta. Pediatr. Dev. Pathol. 12 35–41. 10.2350/08-03-0435.1 - DOI - PubMed
    1. Adam P., Schoof J., Hartmann M., Schwarz S., Puppe B., Ott M., et al. (2007). Cell migration patterns and ongoing somatic mutations in the progression of follicular lymphoma. Cytogenet. Genome Res. 118 328–336. - PubMed
    1. Agraz-Doblas A., Bueno C., Bashford-Rogers R., Roy A., Schneider P., Bardini M., et al. (2019). Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis. Haematologica 104 1176–1188. 10.3324/haematol.2018.206375 - DOI - PMC - PubMed
    1. Alifrangis C., Agarwal R., Short D., Fisher R. A., Sebire N. J., Harvey R., et al. (2013). EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis. J. Clin. Oncol. 31 280–286. 10.1200/JCO.2012.43.1817 - DOI - PubMed
    1. Alizadeh A. A., Aranda V., Bardelli A., Blanpain C., Bock C., Borowski C., et al. (2015). Toward understanding and exploiting tumor heterogeneity. Nat. Med. 21 846–853. 10.1038/nm.3915 - DOI - PMC - PubMed

LinkOut - more resources