Debris-stimulated tumor growth: a Pandora’s box?

Haak, Victoria M; Huang, Sui; Panigrahy, Dipak

doi:10.1007/s10555-021-09998-8

Cited by 21 publications

(15 citation statements)

References 153 publications

(326 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, among those 67 proteins, we found HMGB1 (high mobility group protein B1) (Fig. 3 S) which, in addition to its role as a nuclear non-histone protein is involved in the regulation of transcription and chromatin remodeling, has a critical role as a DAMP that can be secreted outside a cell and participate in the activation of tumor cell repopulation [ 5 , 27 ]. The latter function of HMGB1 allowed us to propose it as a key player in complex with Hsp70.…”

Section: Resultsmentioning

confidence: 99%

“…After receiving a signal, most often from the tumor microenvironment (TME), quiescent cells trigger their intrinsic mechanisms to induce proliferation and terminate the relapse cycle [ 4 ]. The remnants of dying tumor cells or so-called DAMPs (Damage-Associated Molecular Patterns) are found among the inducers of repopulation; these proteins, sometimes also called alarmins, were found to be released from dead or living cells [ 5 ]. However, it is not entirely clear how the debris of dying tumor cells or alarmins can induce proliferation and further relapse.…”

Section: Introductionmentioning

confidence: 99%

“…The process of calreticulin translocation to the surface of tumor cells treated with certain therapeutic factors involves the secretion of ATP, Hsp70/90 and HMGB1 into the medium [ 11 ]. Importantly, the mechanisms governed by the three above alarmins in tumor and TME cells are linked to each other and involve other participants in the relapse process, like caspase-3 [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

“…More notably, increased expression of pro-apoptotic proteins was also observed in low-dose treatments that induced the promotion of tumor growth. Emerging evidence has indicated that cell apoptosis could facilitate tumor growth and is correlated with poor prognosis and disease-free survival in certain types of cancer such as breast, head and neck, and colon cancer ( 46 , 47 ). Chang et al ( 28 ) demonstrated that 5-FU-generated tumor cell debris stimulated tumor growth by triggering the release of OPN from tumor cells in subcutaneous and orthotopic models of colon cancer.…”

Section: Discussionmentioning

confidence: 99%

Dual‑directional effect of vinorelbine combined with cisplatin or fluorouracil on tumor growth and metastasis in metronomic chemotherapy in breast cancer

Liu,

Li,

Lin

et al. 2023

Int J Oncol

View full text Add to dashboard Cite

Metronomic chemotherapy (MCT) regimens may be associated with risks to the patient due to the ambiguity surrounding low dosages and schedules. In the present study, metronomic regimens of vinorelbine (NVB) combined with cisplatin (CDDP) or fluorouracil (5-FU) were chosen to study the dose-response associations with tumor growth and metastasis, along with the underlying mechanisms in angiogenesis, apoptosis and tumor immunity, using experimental techniques such as immunofluorescence, immunohistochemistry, western blotting and flow cytometry. The results demonstrated a dual-directional pharmacological action of promoting and suppressing tumor growth or metastasis in BALB/c mice bearing a 4T1 tumor at certain low and high doses of the drugs. Low doses of NVB combined with CDDP or 5-FU accelerated tumor growth by enhancing angiogenesis, increasing the expression of angiogenic proteins, NF-κB and osteopontin in tumor tissues, and inducing the accumulation of myeloid-derived suppressor cells and macrophages. By contrast, higher doses inhibited tumor growth by suppressing these effects. Notably, the upregulation of apoptotic proteins was observed after low- and high-dose treatments. Furthermore, at low concentrations, NVB combined with CDDP or 5-FU stimulated certain functions of endothelial and tumor cells, including migration and invasion, whereas at higher concentrations they suppressed proliferation and induced apoptosis. Therefore, the results of the present study suggested the potential risks of metronomic combination chemotherapy by demonstrating that, at certain low doses, tumor growth or metastasis was promoted, and emphasized the existence of an effective dose interval that changes with different drug combinations. However, further studies are needed before a specific metronomic combination regimen can be administered clinically for cancer treatment.

show abstract

“…Within this pro-inflammatory milieu, tumor cells can proliferate while circumventing death and invading new tissues by releasing growth factors, survival factors, and proangiogenic factors [39,[83][84][85][86][87]. Several pro-inflammatory mediators, such as TNF-α, IL-6, transforming growth factor beta (TGF-β), IL-10, CCL2, and CCL20, have been shown to attract macrophages and participate in both the initiation and progression of cancer [82,88,89].…”

Section: Inflammation In Cancermentioning

confidence: 99%

COVID-19 and cancer: start the resolution!

Barksdale

Kipper

Tripathy

et al. 2022

Cancer Metastasis Rev

Self Cite

View full text Add to dashboard Cite

Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an ongoing pandemic causing significant morbidity and mortality worldwide. The “cytokine storm” is a critical driving force in severe COVID-19 cases, leading to hyperinflammation, multi-system organ failure, and death. A paradigm shift is emerging in our understanding of the resolution of inflammation from a passive course to an active biochemical process driven by endogenous specialized pro-resolving mediators (SPMs), such as resolvins, protectins, lipoxins, and maresins. SPMs stimulate macrophage-mediated debris clearance and counter pro-inflammatory cytokine production, a process collectively termed as the “resolution of inflammation.” Hyperinflammation is not unique to COVID-19 and also occurs in neoplastic conditions, putting individuals with underlying health conditions such as cancer at elevated risk of severe SARS-CoV-2 infection. Despite approaches to block systemic inflammation, there are no current therapies designed to stimulate the resolution of inflammation in patients with COVID-19 or cancer. A non-immunosuppressive therapeutic approach that reduces the cytokine storm in patients with COVID-19 and cancer is urgently needed. SPMs are potent immunoresolvent and organ-protective lipid autacoids that stimulate the resolution of inflammation, facilitate clearance of infections, reduce thrombus burden, and promote a return to tissue homeostasis. Targeting endogenous lipid mediators, such as SPMs, offers an entirely novel approach to control SARS-CoV-2 infection and cancer by increasing the body’s natural reserve of pro-resolving mediators without overt toxicity or immunosuppression.

show abstract

Debris-stimulated tumor growth: a Pandora’s box?

Cited by 21 publications

References 153 publications

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

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

Dual‑directional effect of vinorelbine combined with cisplatin or fluorouracil on tumor growth and metastasis in metronomic chemotherapy in breast cancer

COVID-19 and cancer: start the resolution!

Contact Info

Product

Resources

About