Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer

Gatenby, Robert A.; Smallbone, Kieran; Maini, Philip K.; Rose, Felicity R. A. J.; Averill, J.H.; Nagle, Raymond B.; Worrall, Lisa K.; Gillies, Robert J.

doi:10.1038/sj.bjc.6603922

Cited by 301 publications

(291 citation statements)

References 25 publications

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“…In normoxia, a balanced activation of canonical and HIF-2-specific pathways tightly controls energy homeostasis and cellular proliferation (Figure 8a). Tumor cells, however, encounter periods of severe oxygen starvation, ultimately selecting for phenotypes resistant to a hostile environment (Gatenby et al, 2007). Thus, cancer cells expressing high levels of HIF-2a (like those cells with suppressed HIF-1a in our study) might benefit from increased autocrine and paracrine growth factor signaling, supporting cellular autonomy by masking unfavorable growth conditions.…”

Section: Discussionmentioning

confidence: 79%

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

et al. 2011

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Tumor progression is intrinsically tied to the clonal selection of tumor cells with acquired phenotypes allowing to cope with a hostile microenvironment. Hypoxiainducible factors (HIFs) master the transcriptional response to local tissue hypoxia, a hallmark of solid tumors. Here, we report significantly longer patient survival in breast cancer with high levels of HIF-2a. Amphiregulin (AREG) and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly HIF2a-dependent and their promoters were particularly responsive to HIF-2a. The endogenous AREG promoter recruited HIF-2a in the absence of a classical HIF-DNA interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG expression in HIF-2a-depleted cells was accompanied by reduced activation of epidermal growth factor (EGF) receptor family members. Apparently opposing results from patient and in vitro data point to an HIF-2a-dependent auto-stimulatory tumor phenotype that, while promoting EGF signaling in cellular models, increased the survival of diagnosed and treated human patients. Our findings suggest a model where HIF2a-mediated autocrine growth signaling in breast cancer sustains a state of cellular self-sufficiency, thereby masking unfavorable microenvironmental growth conditions, limiting adverse selection and improving therapy efficacy. Importantly, HIF-2a/AREG/WISP2-expressing tumors were associated with luminal tumor differentiation, indicative of a better response to classical treatments. Shifting the HIF-1/2a balance toward an HIF-2-dominated phenotype could thus offer a novel approach in breast cancer therapy.

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Section: Discussionmentioning

confidence: 79%

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

et al. 2011

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“…Diffusion limits tumor size. Lack of oxygen in these high-grade tumors would drive hypoxia-inducible factors and cell migration, leading to penetration of the ductal wall and infiltration of the tumor in the breast stroma, as has been previously reported [21,22].…”

Section: Resultsmentioning

confidence: 96%

“…When these tumors involve ducts with a radius larger than L, proliferation is reduced and ischemic necrosis occurs. Lack of oxygen has been postulated to drive hypoxia-inducible factors leading to penetration of the ductal wall and infiltration of the tumor in the breast stroma [21,22]. This may explain the correlation of grade and necrosis with invasion.…”

Section: Discussionmentioning

confidence: 99%

“…Previous mathematical and computational models of DCIS have focused on a single breast duct and have been successful in recapitulating certain features of the spatio-temporal dynamics of proliferating and motile tumor cells at this microscale [18][19][20][21][22][23][24][25][26][27][28][29], and have even, in some cases, been capable of extrapolating their results to predictions of macroscopic growth features [24] or invasive potentials as a function of grade [29]. Here we adopt a multiscale approach to predict growth and size of the volume of breast containing ducts with DCIS based on molecular measurements from histopathology of individual patient tumors.…”

Section: Methodsmentioning

confidence: 99%

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A Novel, Patient-Specific Mathematical Pathology Approach for Assessment of Surgical Volume: Application to Ductal Carcinomain situof The Breast

Edgerton

Chuang

Macklin

et al. 2011

Analytical Cellular Pathology

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Abstract. We introduce a novel "mathematical pathology" approach, founded on a biophysical model, to identify robust patientspecific predictors of tumor growth useful in clinical practice to improve the accuracy of diagnosis/prognosis and intervention. In accordance with biological observations, our model simulates the diffusion-limited in-situ tumors with a relatively short phase of fast initial growth, followed by a prolonged slow-growth phase where tumor size is constrained primarily by the relative weight of cell mitosis and death. The former phase may only last for a few months, so that at the time of diagnosis, we may assume that most tumors will have entered the phase where their size is changing slowly. Based on this prediction, we hypothesize that the volume of breast with ducts affected by in-situ tumors at the time of diagnosis will be closely approximated by a modelderived mathematical function based on the ratio of tumor cell proliferation-to-apoptosis indices and on the extent of diffusion of cell nutrients (diffusion penetration length), which can be measured from immunohistochemical and morphometric analysis of patient histopathology specimens without the need for multiple-time measurements. We tested this idea in a retrospective study of 17 patients by staining breast tumor specimens containing ductal carcinoma in situ for mitosis with Ki-67 and for apoptosis with cleaved caspase-3 and counting cells positive for each marker. We also determined diffusion penetration by measuring the thickness of viable rims of tumor cells within ducts. Using the ensuing ratios, we applied the model to determine a predicted surgical volume or tumor size. We then corroborated our hypothesis by comparing the predicted size of each tumor based on our model with the actual size of the pathological specimen after tumor excision (R 2 = 0.74-0.88). In addition, for the 17 cases studied, both histological grade and mammography were not found to correlate with tumor size (R 2 = 0.08-0.47). We conclude that our mathematical pathology approach yields a high degree of accuracy in predicting the size of tumors based on the mitotic/apoptotic index and on diffusion penetration. By obtaining these ratios at the time of initial biopsy, pathologists can employ our model to predict the size of the tumor and thereby inform surgeons how much tissue to remove (surgical volume). We discuss how results from the model have implications concerning the current debate on recommendations for screening mammography, while the model itself may contribute to better planning of breast conservation surgery.

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“…***Po0.001 versus control condition; **Po0.01 versus control condition; ## Po0.01 versus TTX. Na v 1.5 promotes NHE1-dependent invasiveness L Brisson et al cells to adapt to their high metabolic H þ production (Gatenby et al, 2007). Indeed it has been shown to have a predominant role in extracellular acidification of tumor cells (Bourguignon et al, 2004) and also to be involved in their invasive process (Cardone et al, 2005;Stock and Schwab, 2009;Busco et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

NaV1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H+ efflux in caveolae

et al. 2010

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Na V 1.5 sodium channels enhance the invasiveness of breast cancer cells through the acidic-dependent activation of cysteine cathepsins. Here, we showed that the Na þ /H þ exchanger type 1 (NHE1) was an important regulator of H þ efflux in breast cancer cells MDA-MB-231 and that its activity was increased by Na V 1.5. Na V 1.5 and NHE1 were colocalized in membrane rafts containing caveolin-1. The inhibition of Na V 1.5 or NHE1 induced a similar reduction in cell invasiveness and extracellular matrix degradation; no additive effect was observed when they were simultaneously inhibited. Our study suggests that Na V 1.5 and NHE1 are functionally coupled and enhance the invasiveness of cancer cells by increasing H þ efflux.

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Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer

Cited by 301 publications

References 25 publications

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

A Novel, Patient-Specific Mathematical Pathology Approach for Assessment of Surgical Volume: Application to Ductal Carcinomain situof The Breast

NaV1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H+ efflux in caveolae

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