BBA - Reviews on Cancer (v.1867, #1)

Friend or foe? by Tommaso Colangelo; Giovanna Polcaro; Livio Muccillo; Giovanna D'Agostino; Valeria Rosato; Pamela Ziccardi; Angelo Lupo; Gianluigi Mazzoccoli; Lina Sabatino; Vittorio Colantuoni (1-18).
The network of bidirectional homotypic and heterotypic interactions established among parenchymal tumour cells and surrounding mesenchymal stromal cells generates the tumour microenvironment (TME). These intricate crosstalks elicit both beneficial and adverse effects on tumour initiation and progression unbalancing the signals and responses from the neighbouring cells.Here, we highlight the structure, activities and evolution of TME cells considering a novel colorectal cancer (CRC) classification based on differential stromal composition and gene expression profiles. In this scenario, we scrutinise the molecular pathways that either change or become corrupted during CRC development and their relative prognostic value.Finally, we survey the therapeutic molecules directed against TME components currently available in clinical trials as well as those with stronger potential in preclinical studies. Elucidation of dynamic variations in the CRC TME cell composition and their relative contribution could provide novel diagnostic or prognostic biomarkers and allow more personalised therapeutic strategies.
Keywords: Colorectal cancer; Tumour microenvironment; Stromal cells; Cancer-associated fibroblasts; Immune cells; Cell-cell communications;

Molecular interplay between mutant p53 proteins and autophagy in cancer cells by Marco Cordani; Giovanna Butera; Raffaella Pacchiana; Massimo Donadelli (19-28).
An increasing number of studies highlight the role of mutant p53 proteins in cancer cell growth and in the worsening of cancer patients' clinical outcome. Autophagy has been widely recognized as a main biological event involved in both the regulation of cancer cell proliferation and in the response of several anticancer drugs. A thorough analysis of scientific literature underlines the reciprocal interplay between mutant p53 proteins and autophagy regulation. In this review, we analytically summarize recent findings, which indicate that gain-of-function (GOF) mutant p53 proteins counteract the autophagic machinery by various molecular mechanisms including the regulation of AMPK and Akt/mTOR pathways, autophagy-related genes (ATGs), HIF-1α target genes, and the mitochondrial citrate carrier CIC. Moreover, we report that mutant p53 protein stability is affected by lysosome-mediated degradation through macroautophagy or chaperone-mediated autophagy, suggesting the use of autophagy stimulators to counteract mutant p53 oncogenic activity. Finally, we discuss the functional role of the interplay between mutant p53 proteins and autophagy in cancer progression, a fundamental knowledge to design more effective therapies against cancers bearing mutant TP53 gene.
Keywords: Mutant p53; Autophagy; Cancer;

Caloric restriction - A promising anti-cancer approach: From molecular mechanisms to clinical trials by Gelina S. Kopeina; Vyacheslav V. Senichkin; Boris Zhivotovsky (29-41).
Cancer is the second leading cause of death worldwide and the morbidity is growing in developed countries. According to WHO, > 14 million people per year are diagnosed with cancer and about 8 million die. Anti-cancer strategy includes chemo-, immune- and radiotherapy or their combination. Unfortunately, these widely used strategies often have insufficient efficacy and significant toxic effects on healthy cells. Consequently, the improvement of treatment approaches is an important goal. One of promising schemes to enhance the effect of therapy is the restriction of calorie intake or some nutrients. The combination of caloric restriction or its chemical mimetics along with anti-cancer drugs may suppress growth of tumor cells and enhance death of cancer cells. That will allow the dose of therapeutic drugs to be decreased and their toxic effects to be reduced. Here the possibility of using this combinatory therapy as well as the molecular mechanisms underlying this approach will be discussed.Display Omitted
Keywords: Cancer; Caloric restriction; Chemotherapy; Programmed cell death;

Targeted inhibition of WRN helicase, replication stress and cancer by Natalie Orlovetskie; Raphael Serruya; Ghada Abboud-Jarrous; Nayef Jarrous (42-48).
WRN helicase has several roles in genome maintenance, such as replication, base excision repair, recombination, DNA damage response and transcription. These processes are often found upregulated in human cancers, many of which display increased levels of WRN. Therefore, directed inhibition of this RecQ helicase could be beneficial to selective cancer therapy. Inhibition of WRN is feasible by the use of small-molecule inhibitors or application of RNA interference and EGS/RNase P targeting systems. Remarkably, helicase depletion leads to a severe reduction in cell viability due to mitotic catastrophe, which is triggered by replication stress induced by DNA repair failure and fork progression arrest. Moreover, we present new evidence that WRN depletion results in early changes of RNA polymerase III and RNase P activities, thereby implicating chromatin-associated tRNA enzymes in WRN-related stress response. Combined with the recently discovered roles of RecQ helicases in cancer, current data support the targeting prospect of these genome guardians, as a means of developing clinical phases aimed at diminishing adaptive resistance to present targeted therapies.
Keywords: WRN helicase; RNase P; EGS; Selective cancer therapy; Replication stress; DNA repair;

Brain metastasis: Unique challenges and open opportunities by Frank J. Lowery; Dihua Yu (49-57).
The metastasis of cancer to the central nervous system (CNS) remains a devastating clinical reality, carrying an estimated survival time of less than one year in spite of recent therapeutic breakthroughs for other disease contexts. Advances in brain metastasis research are hindered by a number of factors, including its complicated nature and the difficulty of modeling metastatic cancer growth in the unique brain microenvironment. In this review, we will discuss the clinical challenge, and compare the merits and limitations of the available models for brain metastasis research. Additionally, we will specifically address current knowledge on how brain metastases take advantage of the unique brain environment to benefit their own growth. Finally, we will explore the distinctive metabolic and chemical characteristics of the brain and how these paradoxically represent barriers to establishment of brain metastasis, but also provide ample supplies for metastatic cells' growth in the brain. We envision that multi-disciplinary innovative approaches will open opportunities for the field to make breakthroughs in tackling unique challenges of brain metastasis.
Keywords: Brain metastasis; Central nervous system; Cancer models; Metabolism; Tumor-microenvironment interaction;

Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer by Tariq A. Bhat; Ajay K. Chaudhary; Sandeep Kumar; Jordan O’Malley; Joseph R. Inigo; Rahul Kumar; Neelu Yadav; Dhyan Chandra (58-66).
Abrogation of endoplasmic reticulum (ER) protein folding triggered by exogenous or endogenous factors, stimulates a cellular stress response, termed ER stress. ER stress re-establishes ER homeostasis through integrated signaling termed the ER-unfolded protein response (UPRER). In the presence of severe toxic or prolonged ER stress, the pro-survival function of UPRER is transformed into a lethal signal transmitted to and executed through mitochondria. Mitochondria are key for both apoptotic and autophagic cell death. Thus ER is vital in sensing and coordinating stress pathways to maintain overall physiological homeostasis. However, this function is deregulated in cancer, resulting in resistance to apoptosis induction in response to various stressors including therapeutic agents. Here we review the connections between ER stress and mitochondrial apoptosis, describing potential cancer therapeutic targets.
Keywords: Mitochondria; Apoptosis; Autophagy; Endoplasmic reticulum; Unfolded protein response;