Impact of minimal residual disease on relapse in childhood acute lymphoblastic leukemia: Lessons learnt from a tertiary cancer center in India

Mishra, Varsha; Jain, Sandeep; Anand, Vaneet; Malhotra, Payal; Tejwani, Narender; Kapoor, Gauri

doi:10.1080/08880018.2023.2186553

Cited by 4 publications

(4 citation statements)

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“…Furthermore, several reports have comprehensively demonstrated that, in addition to other extrinsic factors, dying cancer cells themselves are able to impact tumor relapse [ 12 , 17 , 34 ]. In our research, we first confirmed the results of these groups and secondly found that a factor that could stimulate the proliferation of a tiny population of tumor cells imitating so called minimal residual disease [ 19 ] can occur in the CM of cancer cells subjected to chemotherapy; this was established in both in vitro and in vivo experiments and formed the basis of our research model. Of note, autocrine regrowth effect, e.g.…”

Section: Discussionsupporting

confidence: 78%

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Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex

Sverchinsky,

Alhasan,

Mikeladze

et al. 2023

J Exp Clin Cancer Res

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Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence.

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Section: Discussionsupporting

confidence: 78%

“…In conclusion, CM collected from etoposide-treated, dying cells was capable of inducing proliferation in rearely seeded cancer cells imitating minimal residual disease [ 19 ] Mishra et al, 2023]…”

Section: Resultsmentioning

confidence: 99%

Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex

Sverchinsky,

Alhasan,

Mikeladze

et al. 2023

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…Furthermore, several reports have comprehensively demonstrated that, in addition to other extrinsic factors, dying cancer cells themselves are able to impact tumor relapse [12,18,35]. In our research, we rst con rmed the results of these groups and secondly found that a factor that could stimulate the proliferation of a tiny population of tumor cells imitating so called minimal residual disease [20] can occur in the CM of cancer cells subjected to chemotherapy; this was established in both in vitro and in vivo experiments and formed the basis of our research model. Of note, autocrine regrowth effect, e.g.…”

Section: Discussionsupporting

confidence: 72%

“…In conclusion, CM collected from etoposide-treated, dying cells was capable of inducing proliferation in rearely seeded cancer cells imitating minimal residual disease [20] Mishra et al, 2023] Hsp70 is critical for tumor cells repopulation Tumors of different histogenesis often exhibit elevated Hsp70 expression [8]. The protein is believed to constitute a basis for the chaperone mechanism and e ciently protects cancer cells by binding proteins responsible for the execution of apoptosis; moreover, Hsp70 has been found to release from tumor cells, playing the role of a DAMP [21].…”

Section: Resultsmentioning

confidence: 83%

Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex

Sverchinsky,

Alhasan,

Mikeladze

et al. 2023

Preprint

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Background. Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods. Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results. It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions. These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence.

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