Clinical observations on chemotherapy curable malignancies: unique genetic events, frozen development and enduring apoptotic potential

Abstract

BackgroundA select number of relatively rare metastatic malignancies comprising trophoblast tumours, the rare childhood cancers, germ cells tumours, leukemias and lymphomas have been routinely curable with chemotherapy for more than 30 years. However for the more common metastatic malignancies chemotherapy treatment frequently brings clinical benefits but cure is not expected. Clinically this clear divide in outcome between the tumour types can appear at odds with the classical theories of chemotherapy sensitivity and resistance that include rates of proliferation, genetic development of drug resistance and drug efflux pumps. We have looked at the clinical characteristics of the chemotherapy curable malignancies to see if they have any common factors that could explain this extreme differential sensitivity to chemotherapy.DiscussionIt has previously been noted how the onset of malignancy can leave malignant cells fixed with some key cellular functions remaining frozen at the point in development at which malignant transformation occurred. In the chemotherapy curable malignancies the onset of malignancy is in each case closely linked to one of the unique genetic events of; nuclear fusion for molar pregnancies, choriocarcinoma and placental site trophoblast tumours, gastrulation for the childhood cancers, meiosis for testicular cancer and ovarian germ cell tumours and VDJ rearrangement and somatic hypermutation for acute leukemia and lymphoma. These processes are all linked to natural periods of supra-physiological apoptotic potential and it appears that the malignant cells arising from them usually retain this heightened sensitivity to DNA damage. To investigate this hypothesis we have examined the natural history of the healthy cells during these processes and the chemotherapy sensitivity of malignancies arising before, during and after the events.SummaryTo add to the debate on chemotherapy resistance and sensitivity, we would argue that malignancies can be functionally divided into 2 groups. Firstly those that arise in cells with naturally heightened apoptotic potential as a result of their proximity to the unique genetic events, where the malignancies are generally chemotherapy curable and then the more common malignancies that arise in cells of standard apoptotic potential that are not curable with classical cytotoxic drugs.

Chemotherapy curable malignancies and cancer stem cells: a biological review and hypothesis

“…Whilst the hierarchical stem cells will share many characteristics with the tissue specific somatic stem cells from which they arise, the stochastic stem cells arising from within the cancer cell pool whilst taking on some of the acquired characteristics of stemness, will also take on some of the primary biological properties of the malignant cell [53]. We would argue that the stochastic cancer stem cell in taking on key biological traits of the parent cancer cell from which they arise would include assuming the inherent apoptotic sensitivity of the malignant cell linked to the unique genetic event that is associated with each chemotherapy curable cancer type [4]. …”

“…Whilst in this situation there can be no hierarchical cancer stem cells, as these cells arise from the first point in embryological development, recent work has indicated the presence of cancer cells with stem like properties developing within trophoblast cell lines [64]. We would suggest that the cells with stem like properties in this malignancy will share the innate sensitivity to chemotherapy that the trophoblast cells have naturally due to their close temporal relationship with the unique genetic event of nuclear fusion and the associated apoptotic sensitivity [4]. …”

“…Beginning in the 1950s and fully established by the 1980s there has been the development of routine curative chemotherapy treatment for most patients with acute leukemia, high grade non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease, testicular and ovarian germ cell tumors, the gestational trophoblast tumors and for many cases of the rare childhood malignancies [2, 4]. In current practice the cure rates for a number of these diagnoses is in excess of 90%, with the first line cytotoxic drug treatment of each malignancy comprised entirely of drugs developed by the early 1980s.…”

“…The theory centres on the close association between the cells of the chemotherapy curable malignancies and the occurrence of their unique genetic events of nuclear fusion, meiosis, variable-diversity-joining (VDJ) recombination, and somatic hypermutation (SHM) each of which has naturally upregulated apoptotic pathways as shown in Table 1 [3, 4]. In this updated review we will examine the relationship between cancer stem cell biology, the developmental pathways of the chemotherapy curable malignancies and the potential impact these have on the natural apoptotic sensitivity of the cancer stem cells in the differing diagnoses.…”

“…These events are nuclear fusion for gestational trophoblast tumors, meiosis for germ cell tumours, VDJ recombination for ALL and anaplastic lymphoma kinase (ALK) + ve T cell NHL, somatic hypermutation (SHM) for DLBCL, Hodgkin’s disease and Burkitt’s lymphoma and gastrulation for the rare childhood malignancies. Based on the assumption that the onset of malignancy occurs closely related to these events, we have postulated the persistence of the naturally upregulated pro-apoptotic machinery associated with these events remaining active and that this may be a likely major contributor to the ease of cure of these malignancies with chemotherapy treatment [4]. …”