in recent years , we have witnessed a profound revolution in the way we approach and treat renal cell carcinoma ( rcc ) . in a relatively short time ( 10 years , approximately ) , we have gone from a very limited range of therapeutic options [ essentially limited to interferon ( ifn ) and , for the few patients fit enough to receive it , high - dose interleukin-2 ( il-2 ) or , more recently , allogeneic bone marrow transplant ] to almost a plethora of effective agents ( at least 6 drugs currently approved for the treatment of advanced rcc and more to come shortly ) , that has led to define the uncertainties in treatment choices as the ' embarrassment of the riches ' . such a revolution stems from a much improved understanding of rcc biology , predominantly at the cancer cell level , that has led to the recognition of common molecular themes underlying rcc pathogenesis and to the identification of relevant therapeutic targets , such as the activation of pro - angiogenic and of the mammalian target of rapamycin ( mtor ) pathways 1 . successful pharmacological targeting of these pathways has dramatically improved the management of patients with metastatic rcc , who have now access to many different treatment choices across multiple lines of treatment , resulting in a striking prolongation of disease control , in most cases compatible with an acceptable quality of life , as well as in a life expectancy that approaches three years from the diagnosis of metastatic disease in the majority of patients . as a consequence , rcc has gone from a ' orphan ' disease to a paradigm for the successful development of biology - driven therapies and currently constitutes a unique case among solid tumors , as the management of metastatic disease is entirely based on different classes of molecularly targeted drugs . exciting successes notwithstanding , several issues remain to be addressed in the treatment of advanced rcc : 1 ) even in patients who obtain striking clinical responses early in the course of treatment , disease will ultimately escape control and progress to a treatment - resistant state , leading to therapeutic failure ; 2 ) prolonged disease control usually requires ' continuous ' treatment , even across different treatment lines , making the impact of chronic , low - grade , toxicities on quality of life greater and precluding , for most patients , the possibility of experiencing ' drug - free holidays ' ; 3 ) although we have successfully identified classes of drugs ( or molecular mechanisms of action ) that are effective in a substantial proportion of patients , we still fall short of molecular predictive factors that identify individual patients who will ( or will not ) benefit from a specific intervention and still proceed on a trial - and - error basis , far from a truly ' personalized ' therapeutic approach ; 4 ) finally ( and perhaps most importantly ) , even in the best case scenario , currently available treatments inevitably fail to definitively ' cure ' metastatic rcc patients . one of the possible avenues to address such issues , possibly leading to further improvements in the management of advanced rcc , is to better understand the interplay between cancer cell biology , host response , and treatment - induced changes . indeed , the presence of rcc actually shapes host response ( e.g. in terms of immune reaction and microenvironmental changes ) , which , in turn , influences tumor biology ( e.g. in terms of pathway activation ) , in a complex interplay that is just starting to emerge ; in addition , targeted therapies modify both cancer biology and host response , thereby adding a further level of complexity that we are only beginning to appreciate . unraveling such complex interactions may hold the key to future advances in the comprehension of rcc biology and in the treatment of patients with this disease . the term rcc encompasses a highly heterogeneous group of malignancies , from both a morphological and a molecular point of view , but emerging evidence indicates that common molecular paths to renal carcinogenesis do exist and may justify , to some extent , shared approaches to the clinical treatment of different rcc subtypes 2 . although most of rcc cases occur in a sporadic form , both clear cell and non - clear cell rcc can occur in the context of inherited cancer syndromes , whose molecular genetics has shed light on potentially common molecular pathogenetic themes 3 - 4 . this is probably best exemplified by von hippel - lindau disease ( vhl ) and tuberous sclerosis ( ts ) , two autosomal dominant inherited syndromes with variable penetrance that carry a high lifetime risk of developing clear cell rcc 5 - 6 . the vhl gene , which targets hypoxia inducible factor ( hif)-1 for degradation by the proteasome , is mutated or silenced in up to 75% of sporadic clear cell rcc , suggesting that genetic abnormalities involved in inherited rcc syndromes ( and subsequent alterations in downstream intracellular signaling cascades ) may also play a central role in sporadic rcc . in tumors carrying a mutated vhl , increased levels of hif-1 play a critical oncogenic role by stimulating the transcription of many crucial downstream effectors , including vascular endothelial growth factor ( vegf ) , platelet - derived growth factor ( pdgf ) , c - met , transforming growth factor ( tgf)- , and the stromal - derived factor ( sdf)-1/cxcr4 ligand / receptor pair , among others 7 . of note , signaling pathways initiated by such effectors , vegf and pdgf in particular , are the therapeutic targets of monoclonal antibodies and small - molecule kinase inhibitors ( tkis ) that currently constitute the mainstay of clinical rcc treatment . ts , on the other hand , is an autosomal dominant disorder with 95% penetrance , caused by mutations in either the tsc1 ( 9q34 ) or the tsc2 ( 16p13.3 ) genes , encoding for the hamartin and tuberin proteins , respectively . hamartin and tuberin physically interact to form a complex , which , through the gap activity of tuberin , inactivates the small g - protein rheb , thereby relieving rheb - mediated mtor inhibition . therefore , genetic inactivation of tsc1/2 results in the uncontrolled activation of the mtor pathway , leading , among other effects , to increased synthesis and accumulation of hif , even in the absence of hypoxia , and transcription of hif - dependent genes 8 - 9 . indeed , activated mtor , may exacerbate the loss of vhl function ( or the effects of hypoxia ) by further elevating hif-1 through increased translation , thus providing a direct link between the hif / angiogenesis and the mtor paths to renal carcinogenesis . because unregulated angiogenesis is a prominent feature of rcc , the inhibition of mtor is relevant clinically and may inhibit angiogenesis through a mechanistic approach that differs from that of vegf receptor - targeted agents . in addition to clear cell rcc , the spectrum of renal manifestations in ts also includes development of multiple angiomyolipomas , renal cysts , and non - clear cell rcc ( papillary and chromophobe carcinomas ) . other hereditary rcc syndromes involving non - clear cell rcc have also been identified and characterized in terms of the underlying genetic lesions ; interestingly , increased hif expression and transcriptional activity activation of the mtor pathway both appear to be central to the development of different renal manifestations of disease , including benign ( angiomyolipomas , renal cysts , oncocytomas ) , borderline ( hybrid oncocytic tumors ) , and frankly malignant ( papillary and chromophobe rcc ) lesions 10 . genetic aberrations in tsc1/2 and birt - hogg - dub ( bhd ) directly impinge on the activation of the mtor pathway , leading to the development of an array of renal lesions that can be partially reversed by rapamycin - mediated inhibition of mtor , both in preclinical models and human patients with tsc ; in the highly aggressive papillary type 2 rcc observed in hereditary leiomyomatosis and renal cell cancer ( hlrcc ) , fumarate hydratase ( fh ) deficiency creates a pseudohypoxic intracellular environment 9 , leading to hif accumulation ; from a molecular standpoint , this situation is similar to that observed in vhl mutant rcc cells , where hif-1 translation and accumulation can be prevented by mtor inhibition , thereby rendering hif - overexpressing cells particularly prone to the growth inhibitory effects of mtor inhibitors , both in vitro and in vivo . more recently , computational analysis of gene expression data derived from papillary rcc revealed that a transcriptional signature indicative of myc pathway activation is present in high - grade type 2 papillary rcc . the myc signature was associated with amplification of chromosome 8q and overexpression of myc that maps to chromosome 8q24 and , reflective of the association of an active myc signature component with papillary type 2 , the presence of this pathway signature component was also associated with a highly aggressive clinical behavior and poor overall survival 11 . recent evidence indicates the existence of an important growth - regulatory crosstalk between the myc , hif , and the mtor pathway : indeed , both hif-1 and hif-2 may directly or indirectly control myc activity , on one hand , and tuberin loss may de - repress myc protein , on the other , positioning the connection between these two growth regulators to act as a feed - forward loop that would amplify the oncogenic effects of decreased tuberin or increased myc expression 12 . overall , both genetic and molecular data strongly indicate that common avenues do exist in renal carcinogenesis and that hif accumulation and mtor activation represent common molecular themes across a spectrum of both benign renal lesions and different rcc subtypes , including both clear cell and non - clear cell forms , and thus constitute widespread therapeutic targets in both sporadic and familial rcc . understanding ( and overcoming ) primary and/or acquired resistance to both hif / vegf- and mtor - targeted agents is perhaps the most important issue to address , in order to make further clinical progresses in the management of advanced rcc . while the molecular mechanisms of primary resistance are still elusive , clues to the development of acquired resistance in patients that initially respond favorably to vegf / vegf receptor - targeted agents are starting to emerge 13 - 14 . first , the pathway may be incompletely blocked , due to an intrinsically low potency of the agent employed as first - line or to an adaptive response that leads to increased drug metabolism / extrusion , with consequently reduced effective drug levels , or to increased signaling through the same ligand / receptor pairs that are being targeted ( in most cases vegf / vegfrs and pdgf / pdgfrs ) ; such a resistance mechanism would explain the clinical finding of incomplete cross - resistance between vegf / vegfr - targeted drugs , particularly when crossing over to a second - line agent more potently targeting the same pathway . second , under the selective pressure of prolonged treatment with anti - angiogenic agents ( mostly targeting the vegf axis ) , rcc may ultimately resume an angiogenic state either by increasing hif - mediated transcription of vegf and pdgf or through alternative , non hif - mediated pro - angiogenic factors , such as fibroblast growth factor ( fgf ) , interleukin-8 ( il-8 ) , placental - derived growth factor ( plgf ) , angiopoetins , etc . ; in these cases , the tumor would still depend on its ability to stimulate angiogenesis , thus targeting hif directly or the alternate angiogenic pathway(s ) in sequence could still lead to disease control . third , rcc cells may adapt to an intrinsically hypoxic , anti - angiogenic , microenvironment by activating intracellular signaling pathways , such as the mtor pathway , that would help them coping with a state of high metabolic stress , while maintaining their ability to grow ; the development of resistance through this molecular mechanism actually constitutes the rationale for sequential ( or alternating ) vegf / mtor pathway targeting , that is becoming increasingly popular in the clinical setting ( see below ) . in addition to cancer cell - centered mechanisms of resistance , a potentially important and relatively unexplored area of research is the contribution of host - derived microenvironment to the ability of tumors to adapt to prolonged blockade of vegf - mediated angiogenesis and escape from anti - angiogenic drug mediated growth control 15 . for example , increased host - derived pericyte coverage and recruitment of bone marrow - derived cell populations ( that are ' normal ' in nature ) may protect tumor blood vessels and endorse restored neo - vascularization , even in the presence of continuous vegf blockade ; interestingly , activity of the hif family of transcription factors appears to play a crucial role not only in the biology of the rcc cell itself , but also in orchestrating the response of host - derived cells to prolonged anti - angiogenesis , thereby constituting a potential therapeutic target whose direct inhibition may simultaneously hit both the cancer cell and the surrounding microenvironment . finally , in the presence of a hostile , anti - angiogenic , microenvironment the rcc cell may acquire a more motile , invasive , phenotype that allows it escaping nutrient and oxygen deprivation by metastasizing to different organs where they could hijack host - derived protective mechanisms to create a more favorable environment 16 . studies conducted in tumors that have become resistant to sunitinib - mediated anti - angiogenesis , indeed , indicate that resistant tumor cells acquire a ' sarcoma - like ' phenotype , with decreased cytokeratin and increased vimentin expression ( indicative of an epithelial - to - mesenchymal transition - emt ) , invade surrounding tissues , and display decreased vascular density 17 . metabolic adaptation to stress conditions is an important mechanism involved in tumor progression and development of resistance mechanisms . a solid tumor can outstrip its nutrient and oxygen supply as it grows , resulting in metabolic stress . as a consequence , tumor cells must undergo a period of metabolic adaptation to survive this stress or undergo apoptosis ; angiogenesis and neovascularization is one strategy of metabolic adaptation used by tumors to relieve this stress , while maintaining their capacity to grow indefinitely 18 . by blocking angiogenesis for prolonged periods of time , as it is usually the case for the first - line treatment of metastatic rcc , the tumor is put back in a state of metabolic stress , to cope with which it must activate alternative relief mechanisms . given its strategic position in the regulation of cell growth , metabolism , and angiogenesis , the mtor pathway is a likely candidate to be a crucial regulator of ' metabolic adaptation ' in situations in which the vegf - based angiogenic switch is pharmacologically inhibited . indeed , mtor senses availability of aminoacids , metabolic fuel , and energy ( essential for protein synthesis , cell growth , proliferation , and survival ) and its activation supports growth and survival by increasing cell access to nutrients and metabolic fuels , through increased expression of nutrient transporters . it is , therefore , reasonable to speculate that alternating agents with different modes of action would actually turn tumor 's ability to activate either neo - angiogenesis or mtor signaling to cope with situations of metabolic stress to our advantage : indeed , after prolonged exposure to vegf / vegfr - targeted agents , rcc cells may activate mtor to cope with metabolic stress and survive ; if mtor is blocked at this stage , tumor cells would be most sensitive to its action and would go back to a neo - angiogenesis driven response to metabolic stress , again becoming sensitive to vegf - targeted strategies . although such hypothesis remains to be tested , both experimentally and clinically , solid clinical evidence indicates that mtor inhibitors are effective after progression to vegf / vegfr - targeted strategies and initial reports suggest that rechallenge with a vegfr tki ( even the same agent used as first - line ) after an mtor inhibitor may lead to substantial clinical benefit . another dimension , that is only now starting to emerge from the literature , is the complex interplay between the cancer cell(s ) , the host immune system , and the molecularly targeted agents that are used for treatment . it is relatively well known that the presence of a tumor may shape host immune response by creating an immunosuppressive environment ; in the specific case of rcc , which is characterized by prominent activation of the hif / vegf axis , vegf itself and/or other cytokines produced by tumor cells exert profound immunosuppressive effects by impairing dendritic cell maturation from myeloid progenitors , increasing treg - mediated suppression of t - cell responses , and shifting the balance towards a th2 type of response with secondary production of il-10 , il-4 , and il-6 . not only tumors , including rcc , may effectively suppress tumor - specific immune responses , but they can also hijack host - derived cell populations , turning them into powerful allies that help creating a pro - angiogenic , tumor - promoting microenvironment 19 : indeed , tumor - infiltrating macrophages , neutrophils , dendritic cells ( dcs ) , and natural killer cells may shift from the production of anti - angiogenic / tumor suppressing cytokines , such as ifn- and il-12 , to the secretion of vegf , plgf , fgf , pdgf , il-8 , matrix metalloproteases ( mmps ) , cyclooxygenase-2 ( cox-2 ) , and arginase ; moreover , in the tumor microenvironment myeloid progenitor cells may be forced to differentiate into myeloid - derived stromal cells ( mdscs ) , that potently support tumor - driven vasculogenesis and help protecting tumor - associated neo - vessels from anti - angiogenic therapeutic attack . the immune - modulatory effects of therapeutic agents ( mostly vegf / vegfr and mtor inhibitors ) commonly used to treat rcc are only beginning to surface 20 . for example , two commonly used anti - angiogenic multi - kinase inhibitors , such as sorafenib and sunitinib , clearly differ in their ability to , directly or indirectly , influence immune response : indeed , sorafenib appears to impair , while sunitinib stimulates , terminal dc maturation and ability to co - stimulate t - cell responses ; sunitinib , but not sorafenib , inhibits mdsc immune - suppressive activity , reduces both mdsc and treg circulating numbers , and corrects th2 bias . it would be even more interesting to understand the immunomodulatory effects of rapamycin derivatives , such as temsirolimus and everolimus , in the specific context of rcc treatment , considering their well - established alternative use as immunosuppressants in organ transplantation . in the past ten years we have made exceptional progresses in the understanding of rcc biology , particularly by recognizing the crucial pathogenetic role of activation of the hif / vegf and mtor pathways . this has resulted in the successful clinical development of anti - angiogenic and mtor - targeted drugs , which have profoundly impacted on the natural history of the disease and have improved the duration and quality of rcc patient lives . however , further improvements are still greatly needed , particularly in the quest for ' curative ' treatments , currently lacking in the setting of advanced rcc . as highlighted above , unraveling the complex mechanisms by which rcc shapes host microenvironment and immune response and therapeutic treatments , in turn , shape both cancer cell biology and tumor - host interactions may hold the key to future advances in such a complex and challenging disease .