Hypoxia-mediated drug resistance: Novel insights on the functional interaction of HIFs and cell death pathways

Mhawech‐Fauceglia

Laboratory Investigation

et al. 2013

272

125

For many cancers, there is a real need for more effective therapies. Although many drugs show promising results in vitro, most fail to translate into an in vivo model system, and only B5% show anti-tumor activity in clinical trials. It remains a significant challenge to accurately replicate in vitro the complex in vivo microenvironment in which cancers thrive, but this will be key to increasing the success of translating novel therapies into clinical practice. Three-dimensional (3D) cell culture models may better mimic primary tumors in vivo than traditional two-dimensional (2D) cultures. Therefore, we established and characterized 3D in vitro models of 31 epithelial ovarian cancer (EOC) cell lines, compared their biological and molecular features with 2D cultures and primary tumors, and tested their efficacy as models for evaluating chemoresponse. When cultured in 3D using polyhydroxoethylamethacrylate-coated plastics, EOC lines formed multicellular aggregates that could be classified as 'large dense', 'large loose', and 'small', based on size, light permeability, and proportion of cells incorporated into the complex structures. Features of histological differentiation characteristic of primary tumors that were not present in 2D cultures were restored in 3D. For many cell lines, the transition from a 2D to 3D microenvironment induced changes in the expression of several biomarkers relevant to disease. Generally, EOC cell lines proliferated more slowly and were more chemoresistant in 3D compared with 2D culture. In summary, 3D models of EOCs better reflect the histological, biological, and molecular features of primary tumors than the same cells cultured using traditional 2D techniques; 3D in vitro models also exhibit different sensitivities to chemotherapeutic agents compared with 2D models, which may have a significant impact on the success of drug testing pipelines for EOC. These findings could also impact in vitro modeling approaches and drug development strategies for other solid tumor types. The success rate of anti-cancer therapies translating from in vitro culture systems into the clinic is about 5%. 1 The vast majority of drugs that show promising results in vitro fail to replicate in an in vivo model system and even fewer make it into clinical trials. Nonetheless testing drugs in cell culture models is a vital part of any drug development process. It is likely that a major contributing factor to the low rates of in vivo translation of new therapeutic agents is the widespread use of two-dimensional (2D) monolayer culture systems used for in vitro drug discovery and development. 2D cultures fail to recapitulate the gradients of drugs, nutrients, gases, and waste products that characterize tumors in vivo; all are important factors influencing response to therapy. 2,3 Moreover, many of the signaling pathways involved in chemoresponsiveness are differentially activated in monolayer cultures, and as a result, 2D cultures are often more sensitive to drug therapies yielding many false-positive results in 2D dr...

mentioning

confidence: 99%

A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro

Mhawech‐Fauceglia

Laboratory Investigation

et al. 2013

272

125

“…In the vast majority of transformed cells, HIF1α functions as a robust suppressor of apoptosis and functional interference with HIF1α results in enhanced cell death upon treatment with chemotherapeutic agents in tumors of different origins [70]. The molecular nature of this phenomenon was mostly explained by HIF1α anti-apoptotic target gene-induction (Bak, Bax, Bcl-xL, Bcl-2, Bid, Mcl-1, NF-κB, p53 and survivin), but also by suppression of p53 activation in response to chemotherapeutic agents [71], as it can be seen in Figure 3.…”

Section: Hifs and Cell Death Pathways: Apoptosis And Autophagymentioning

confidence: 99%

The Role of Hypoxia-Inducible Factors in Cancer Resistance

Saint-Martin¹,

Castañeda-Patlán²,

Robles-Flores³

2017

J Cell Signal

Diminished oxygen availability (hypoxia) is a hallmark of the tumor microenvironment. A major regulator of cellular adaptation to hypoxia is the hypoxia-inducible factor (HIF) family of transcription factors, which play key roles in many crucial aspects of cancer biology including angiogenesis, stem cell maintenance, metabolic reprogramming, resistance to apoptosis, autocrine growth factor signaling, the EMT program, invasion and metastasis.Resistance to chemotherapy/radiotherapy is the primary cause for treatment failure in clinical oncology. Hypoxia and accumulation of hypoxia-inducible factors (HIFs) in solid tumors have been associated with resistance to treatment and poor prognosis. HIFs causes autophagy establishment to promote survival of cancer cells, and is also associated with the promotion and maintenance of cancer stem cells, a minority subpopulation within the tumor responsible for tumor recurrence and resistance to chemotherapy.In this review, we provide a concise comparative description of the structure, regulation, transcribed genes and roles played by each HIFα subunit in coordinating the transcriptional responses to hypoxia and on the roles they play in the promotion of resistance to anti-cancer therapy.

Oncology &Amp; Hematology Review (US)

“…16 In the ECAS survey, the level of anemia had a significant impact on performance status and, using the physician-reported WHO performance score, there was a significant correlation between decreasing Hb and worsening performance status. hypoxia is known to confer resistance to some radiation and chemotherapy regimens, 20,21 in turn leading to treatment failures.…”

Section: Detrimental Effect Of Cancer-related Anemiamentioning

confidence: 99%

Iron Deficiency Anemia in Cancer Patients

Janis¹

2012

Anemia is defined by the World Health Organization as a hemoglobin (Hb) level <13 g/dl for men and <12 g/dl for women, 1 and can be further subcategorized into mild (>10 g/dl), moderate (8-10 g/dl), severe (6.5-8 g/dl), and life-threatening (<6.5 g/dl) ranges. Anemia is a common comorbidity in cancer patients. In the previously mentioned ECAS study, cancer-related anemia was most frequently reported in patients with gynecological cancer (81.4 %), lung cancer (77 %), and lymphoma/myeloma (72.9 %). 2 In addition, this study indicated that the longer patients received chemotherapy, the higher their risk of becoming anemic. Anemia is also a recognized complication of myelosuppressive chemotherapy in cancer patients. AbstractAnemia is highly prevalent, affecting approximately 40 % of cancer patients, and results in a significant decrease in health-related quality of life while also being associated with shorter cancer survival times. A recent survey of 15,000 cancer patients in Europe found that 39 % were anemic at the time of enrolment. In addition, anemia is a recognized complication of myelosuppressive chemotherapy, and it has been estimated that, in the US, around 1.3 million cancer patients who are not anemic at the time of diagnosis will develop anemia during the course of their disease. The etiology of anemia in cancer patients is variable and often multifactorial, and may be the result of an absolute or a functional iron deficiency. Cancer produces an enhanced inflammatory state within the body-causing hepcidin levels to increase and erythropoietin production to decrease-and results in a reduction in erythropoiesis due to impaired iron transport. This type of anemia is known as functional iron deficiency, where the body has adequate iron stores but there are problems with mobilization and transport of the iron. Absolute iron deficiency is when both iron stores and iron transport are low. The National Comprehensive Cancer Network (NCCN) treatment guidelines for cancer-related anemia recommend intravenous (IV) iron products alone for iron repletion in cancer patients with absolute iron deficiency, and erythropoiesis-stimulating agents (ESAs) in combination with IV iron in cancer patients (currently undergoing palliative chemotherapy) with functional iron deficiency. Although IV iron has been demonstrated to enhance the hematopoietic response to ESA therapy, the use of supplemental iron has not yet been optimized in oncology. Here we discuss the significance of iron deficiency anemia in cancer patients and the need to implement tools to properly diagnose this condition, and we provide an overview of the management strategies and recommendations for patients with iron deficiency anemia as outlined in the NCCN guidelines.