This article provides an insight on different heat shock proteins and their roles as well as their expression in different brain cancers and tumors. Extensive review of various literatures associated with Brain cancers and heat shock proteins was carried out. All available data suggested abnormal high expression of different classes and families of the proteins in a wide range of brain cancers. Most of the results were also in correspondence with related results of expression of the proteins in other groups of cancers.

Heat shock proteins (HSPs) are belong to a class of proteins that have significant roles in living organisms particularly humans [1]. HSPs are proteins that assist other proteins in folding after their synthesis [2]. Protein folding is a critical process after its synthesis. Unless a protein folds, then it cannot be able to carry out its function. Folding of a protein into three dimensional structures is akin to its function [3]. The 3D structure id the penultimate form for function and proteins that are unfolded or abnormally fold are incapable of their function [4].

HSPs are important component of a cell in most biological processes including cellular stresses, environmental factors, and pathological conditions [5]. These groups of proteins specialize in absorption of heat effects due to extreme temperature, facilitate protein folding, translocation and possibly degradation [6]. HSPs acting to facilitate protein folding are known as Molecular chaperones. HSPs expression has been found to be elevated in many types of Cancer including Breast cancer, colorectal cancer, Lung cancer and cervical cancer [7].

HSPs facilitate protein folding (Figure1) and are otherwise known as molecular chaperones [8]. These proteins are folded either directly after protein translation or after partial denaturation due to environmental factors such as elevated temperature [9]. The folding of many proteins, particularly large ones, is kinetically slow and is HSPs kinetically facilitate the process [10]. Most protein processes are thermodynamically not favorable as they require significant amount of energy.

In a similar mechanism with enzymes and their substrates, the HSPs tend to lower the required energy and make the process thermodynamically feasible. HSPs have therefore been implicated in many cancers and their expression has been studied. This review thus aims to summarize some key HSPs whose expression has been studied in brain cancers.

Heat Shock proteins
Heat shock proteins are also known as stress responsive proteins and are widely found in cells of all eukaryotes [11]. They are a class of proteins that are involved in a number of cellular activities including protein folding, apoptosis, cell proliferation and even protein translocation [12]. Heat shock proteins that assist in protein folding are referred to as molecular chaperones and include HSP10, HSP27, HSP40, HSP60, HSP70, HSP90, HSP110 etc.

Heat shock proteins have been evolutionary conserved in eukaryotes and are name with acronym ‘’HSP’’ linked with their Molecular weight [13]. Some HSPs comprised several proteins forming a family of heat shock proteins. For example HSP70 represents a family of at least eight proteins some of which are tissue-specific and localized in several organelles in eukaryotes while the family includes two proteins in humans [14].

Hsp70 is the most prominent of the HSP70 family and is a 70kDa protein with two functional domains, a 44kDa ATP-Binding domain and a 28kDa C-terminal substrate binding domain [15]. The ATP-Binding domain is conserved in most of the members of the family while the substrate binding domain comprised of two-layered twisted β-sheets [16]. The member of the family is a constitutively expressed, 73kDa protein Hsc70 [14].

Brain Cancers
Brain cancers or tumors refer to cancers of the brain in the central nervous system. The tumors can benign or malignant and ranges from lower to higher ages [23]. Brain tumors are one of the most life-threatening cancers and were reported as the 10th most common cause of death in both men and women around the world [24]. In 2015, about 700,000 people were reported to have been living with brain tumors out of which more than 70% were benign and less than 30 % were malignant [25]. In the first half of this year, about 80,000 new cases of brain cancers have been reported already which included over 20,000 malignant cases and over 50,000 non-malignant ones according to the American Brain tumor association.

Heat Shock protein in Brain cancer and tumors
Heat shock proteins assist many proteins to fold, thus their high expression during cancers, which involves expression of a large number of oncoproteins, is expected [26]. Many studies have indicated high expression of many heat shock protein in breast cancer, head and neck carcinomas and brain tumors [27]. In medulloblastoma, one of the most common malignant brain tumors in children, heat shock protein levels have been found to be elevated and have been implicated in tumor cell proliferation [28].

Similarly, Graner., et al. [29] reported atypical expression pattern of HSP70 in brain tumor cell lines. Their results showed substantial over expression of the heat shock proteins even on the surface of the cells both constitutive and in response to shock conditions. A novel small heat shock protein, Hsp16.2 was remarkably reported to be highly expressed in necroectodermal tumors [30]. Similar result was obtained when the expression of this small heat shock protein was studied in different types of brain tumors including benign and malignant meningeoma, oligodendroglioma, glioblastoma multiforme, ependymoma and medulloblastoma [31].

Mirzaei et al., [32] reported a down regulation of Hsp40 in U-87MG (brain tumor) cell lines when the variant protein Oct4B1 was silenced, suggesting a correlative interaction between expression of the protein and Hsp40. Increased Membrane surface expression of some heat shock proteins at the onset of carcinogenesis suggest a possible role of the proteins in signaling pathways [33]. These and so many studies have described the role of Heat shock protein carcinogenesis of many brain cancers and tumors.

Significance and Potentials of Heat shock proteins in brain cancer therapy
Brain cancers are a major threat in various part of the world [34]. Thus development of various therapeutic approaches is imperative to provide cure to brain carcinomas [35]. Multiple studies have described roles of HSPs in carcinogenesis and tumor progression [36]. Here in our studies, we have the shown roles played by HSPs in various processes of carcinogenesis of brain cancer including anti-apoptosis, angiogenesis and tumor cell proliferation (Figure 2).

Thus these roles can easily be exploited to develop therapeutic agents in brain carcinomas. For example as Alexiou., et al. [37] reported anti-apoptotic roles of HSPs 27, 60, 70 and 90 in medullocarcinomas, a therapeutic agent targeting each of the HSPs could be a promising approach (Figure 3). Similarly certain HSPs have complementary function with one other during protein folding, for instance Hsp70 complements Hsp90 chaperonic activity [38]. As such targeting one of the proteins could have a corresponding effect to the other, therefore achieving higher folds of chaperone inhibition.

As Tutar [14] showed, inhibition of Hsp90 results into overexpression of Hsp27 and Hsp70 in brain cancers such as glioblastomas. However it has been shown that continuous to exposure to inhibitors of Hsp90 resulted into resistance to chemotherapy in gliomas and as well as oligodendroglioma [39]. This could be attributed to overexpression of Hsp70 as a result of Hsp90 inhibition. Therefore exploiting the complementary roles of these HSPs particularly in brain cancers and tumors could be significant in developing efficient therapeutic approach with less chances of resistance.

It is evident from a large number of studies carried out and bulk data available that many Heat shock proteins play crucial roles in carcinogenesis of many malignant and benign brain tumors. Such proteins, giving their roles in folding of proteins (oncoproteins), apoptosis and increased cell survival and also, signaling roles could present a target for therapeutic agents. Inhibitors of some HSPs e.g 17-AAG have already been approved for use in patients with different level of brain tumors [40]. However direct inhibition of an individual HSP might not be as efficient as seen in Hsp90 [41]. Thus use of more diverse approaches in developing inhibitors could be valuable.

Schultz., et al. [41] reported a combine approach of inhibition of HSP27 and pAKT in SPARC-induced glioma cell. Although these approaches have been tested in many forms of brain cancers and tumors particularly gliomas and medulloblastoma, a number of brain cancers have yet to be tried upon by utilizing HSPs as potential therapeutic targets [42]. From our studies, we can conclude that HSPs massive role in promoting brain cancers could spell a potential target for a holistic approach in this complicated group of cancers.

Recommendations
We recommend that more studies on expression of heat shock proteins in different brain tumors. This we enable studies to determine specific classes and families of the protein specifically involved in the development of brain cancers. Similarly, we recommend that such proteins should be targeted as a potential therapeutic measure in management of brain cancers.