Autocrine signaling explains the emergence of Allee effects in cancer cell populations

In many human cancers, the rate of cell growth depends crucially on the size of the tumor cell population. Low, zero, or negative growth at low population densities is known as the Allee effect; this effect has been studied extensively in ecology, but so far lacks a good explanation in the cancer setting. Here, we formulate and analyze an individual-based model of cancer, in which cell division rates are increased by the local concentration of an autocrine growth factor produced by the cancer cells themselves. We show, analytically and by simulation, that autocrine signaling suffices to cause both strong and weak Allee effects. Whether low cell densities lead to negative (strong effect) or reduced (weak effect) growth rate depends directly on the ratio of cell death to proliferation, and indirectly on cellular dispersal. Our model is consistent with experimental observations of brain tumor cells grown at different densities. We propose that further studying and quantifying population-wide feedback, impacting cell growth, will be central for advancing our understanding of cancer dynamics and treatment, potentially exploiting Allee effects for therapy.

A CRAF/glutathione-S-transferase P1 complex sustains autocrine growth of cancers withKRASandBRAFmutations

The Ras/RAF/MEK/ERK pathway is an essential signaling cascade for various refractory cancers, such as those with mutantKRAS(mKRAS) andBRAF(mBRAF). However, there are unsolved ambiguities underlying mechanisms for this growth signaling thereby creating therapeutic complications. This study shows that a vital component of the pathway CRAF is directly impacted by an end product of the cascade, glutathione transferases (GST) P1 (GSTP1), driving a previously unrecognized autocrine cycle that sustains proliferation of mKRASand mBRAFcancer cells, independent of oncogenic stimuli. The CRAF interaction with GSTP1 occurs at its N-terminal regulatory domain, CR1 motif, resulting in its stabilization, enhanced dimerization, and augmented catalytic activity. Consistent with the autocrine cycle scheme, silencing GSTP1 brought about significant suppression of proliferation of mKRASand mBRAFcells in vitro and suppressed tumorigenesis of the xenografted mKRAStumor in vivo. GSTP1 knockout mice showed significantly impaired carcinogenesis of mKRAScolon cancer. Consequently, hindering the autocrine loop by targeting CRAF/GSTP1 interactions should provide innovative therapeutic modalities for these cancers.

Autocrine Growth Hormone (GH)-Mediated Triptolide Resistance Overcame by Metformin Co-Treatment in MDA-MB231 Breast Cancer Cells Through ER Stress Pathway

Breast cancer is the most common cancer in women worldwide and the second most common cancer overall. Autocrine growth hormone (GH) expression induced cell proliferation, growth, invasion-metastasis in vitro and in vivo breast cancer models. Moreover, forced GH signaling acts as a drug resistance profile in breast cancer cell lines against chemotherapeutic drugs such as tamoxifen, mitomycin C, doxorubicin and curcumin. Triptolide, an active plant extract from Tripterygium wilfordii, has been shown to induce apoptotic cell death in various cancer cells such a prostate, colon, breast cancer. Metformin, a common therapeutic agent for type II Diabetes mellitus, has been shown to induce autophagy, endoplasmic reticulum (ER) stress and apoptotic cell death in cancer cells. Our aim is to demonstrate the potential effect of metformin on triptolide-mediated drug resistance in autocrine GH expressing MDA-MB-231 breast cancer cells through Endoplasmic reticulum (ER) stress. Autocrine GH-mediated triptolide (20 nM) resistance overcame by metformin (2 mM) co-teatment in MDA-MB231 breast cancer cells through accelerating cell viability loss, growth inhibition compared to alone triptolide treatment. Combined treatment increased apoptotic cell death via CHOP activation, IRE1α upregulation. Consequently, we suggest that triptolide can be more effective with metformin combination in MDA-MB-231 GH+ drug resistant breast cancer cells.

Therapeutics and prospects of Interleukin 2

Interleukin-2 was discovered back in 1983 as an autocrine growth factor for cultured T cells and was the first biological product created through the use of recombinant DNA. IL-2 tumor immunotherapy performed the first historical clinical demonstration of the possibility to cause an effective anticancer immune reaction, mediated by cytotoxic lymphocytes activated from IL-2 stimulation. The Interleukin 2 receptor is a heterotrimeric protein that is composed of three peptide chains: the alpha chain, the beta chain and the gamma chain of the common cytokine receptor. There are 3 majors’ ways of interfering with the IL-2/IL-2R to use it as treatments: Antibodies, Aptamers, and punctual mutagenesis. Recent studies have shown, that Il-2 therapies for cancer, specifically targets restoring the individual’s natural antitumor immune response. HIV directed treatments have demonstrated the necessity of introducing the IL-2 complemented with the patient’s antiretroviral therapy.

Autocrine Growth Hormone Mediated Curcumin Resistance Overcame by Autophagy Inhibition via Bafilomycin in MDA-MB-231 and T47D Breast Cancer Cells

Curcumin, a plant derived natural compound, has anti-oxidant, anti-proliferative and apoptotic effect on various cancer cells such as prostate, colon and breast cancer. Autocrine growth hormone (GH) expression induced breast cancer invasion-metastasis has been reported in vivo and in vitro cancer models. Autophagy is a vesicule-mediated clearance mechanism and one of the handicap against drug-induced apoptotic cell death. In this study, our aim was to investigate the molecular machinery of curcumin induced apoptotic cell death under autophagy inhibition conditions in autocrine GH expressing MDA-MB-231 and T47D breast cancer cells. Although autocrine GH induced curcumin resistance, this effect was slightly prevented by time-dependent curcumin treatment in MDA-MB-231 and T47D breast cancer cells. In addition, curcumin induced autophagy vacuole formation was determined by acridine orange staining in MDA-MB-231 and T47D wt/GH+ breast cancer cells. Moreover, curcumin triggered autophagy through upregulating Beclin-1, Atg3, Atg12 expressions and LC3 cleavage in each cell line. Concomitantly, BiP, IRE1α and Calreticulin expressions were upregulated following 3 h curcumin exposure in MDA-MB-231 wt and GH+ cells. According to MTT cell viability assay, autocrine GH-mediated curcumin resistance was overcome by bafilomycin and curcumin co-treatment in MDA-MB-231 and T47D GH+ cells. Moreover, curcumin and bafilomycin co-treatment induced cell cycle arrest at G1 phase in MDA-MB-231 GH+ cells, G2/M arrest in T47D GH+ breast cancer cells. In conclusion, autocrine GH-triggered curcumin resistance was overcome by autophagy inhibition condition by bafilomycin treatment in a dose-dependent manner in MDA-MB-231 and T47D GH+ breast cancer cells.

ADRENOMEDULIN DI KARSINOMA PAYUDARA DENGAN METASTASIS

Metastasis is the leading cause of mortality in patients with breast cancer. The molecular biology behind the metastasis is verycomplex and may require changes in the regulation of the cell cycle, protein that promotes autocrine growth loop, and the protein thatcauses epithelial to mesenchymal transition. More complex, it is clear that the biology of metastasis is partly governed by the non-tumourcells, including fibroblasts, endothelial cells and myoepithelial cells. Adrenomedullin is an autocrine growth factor produced by the renalcarcinoma cells. However, previous studies indicated that adrenomedullin can be secreted in various carcinoma tissue and carcinoma cells.Adrenomedullin may mediate immunosuppression, antiapoptosis, angiogenesis and proliferation, thus it is an important tumour cellsurvival factor underlying human carcinoma genesis. The role of adrenomedullin in the carcinoma genesis, invasion and metastasis hasbeen greatly focused. The aim of this study was to determine the concentration of adrenomedullin in patients with metastatic breast cancer.A total of 64 patients with breast cancer aged 21–90 years (63 women and 1 man) in Jakarta has been participated in this study aftersigning informed consent. Metastasis was confirmed by examination of bone scanning. Concentrations of adrenomedullin were measuredby EnzymeLinked Immunosorbent Assay (ELISA) using a commercial kit. Based on examination of bone scanning, there were 24 (37.5%)subjects with metastasis and 40 (62.5%) nonmetastasis. Mean of the concentrations of adrenomedullin in the subjects with metastasiswas 252.5 (205.0–299.9) pg/mL, while in the nonmetastasis was 203.1 (178.7–227.5) pg/mL. The concentrations of adrenomedullinwere significantly higher in subjects with metastasis than nonmetastasis (p=0.041). High concentration of adrenomedullin in the subjectswith metastasis suggests that adrenomedullin may be more likely to be involved in metastasis.