
 bfgfbasic fibroblast growth factorcafcancer - associated fibroblastnatnormal fibroblast basic fibroblast growth factor cancer - associated fibroblast
although genetic mutations in tumor cells are the primary drivers of tumorigenesis , stromal cells in the tumor microenvironment , including fibroblasts , immune cells , and endothelial cells , are active conspirators in promoting tumor growth and metastasis .
oncogenic signaling within tumors frequently drives the recruitment of normal fibroblasts ( nafs ) and reprograms them into cancer - associated fibroblasts ( cafs ) .
cafs are activated fibroblasts that share similarities with fibroblasts and are stimulated by inflammatory conditions or activated during wound healing .
they constitute a significant component of the stroma and mediate changes in the composition of extracellular matrix to one with an increased amount of collagens ( desmoplastic response ) .
cafs are phenotypically and functionally distinct from nafs and can be identified based on the expression of several markers including  smooth muscle actin ( -sma ) , fibroblast activation protein ( fap ) ; fibroblast - specific protein 1 ( fsp1 ) , and platelet - derived growth factor receptor ( pdgfr ) . transforming growth factor  ( tgf- ) , platelet - derived growth factor ( pdgf ) , basic fibroblast growth factor ( bfgf ) , interleukin 6 ( il-6 ) , and lysophosphatidic acid ( lpa ) , which can induce desmoplastic reactions in tumors ,
cafs are functionally distinct from nafs and significantly promote tumor growth in xenograft models when mixed with tumor cells .
the tumor - promoting effects of cafs are mainly mediated through a paracrine mechanism involving multiple secreted factors , including hepatocyte growth factor ( hgf ) , connective tissue growth factor ( ctgf ) , epidermal growth factor ( egf ) , insulin growth factor ( igf ) , nerve growth factor ( ngf ) , bfgf , wingless / integrase-1 ( wnt ) ligands , and matrix metalloproteinase .
in addition to these paracrine events , cafs secrete many chemokines ( such as c - x - c motif chemokine 12 [ cxcl12 ] , cxcl14 , and ccl7 ) and vascular endothelial growth factor ( vegf - a ) to regulate angiogenesis .
for instance , cafs secrete cxcl12 , which binds and activates cxcr4 in tumor cells , to induce migration and proliferation of tumor cells .
in addition , cafs can change their metabolic profile and provide metabolic intermediates that enhance tumor growth .
for example , phosphoglycerate kinase-1 ( pgk1 ) , a component of the glycolytic pathway , is dramatically upregulated in cafs compared with nafs .
overexpression of pgk1 reprograms nafs into cafs , causing a proliferation of cafs , and promotes tumor growth when co - implanted in vivo .
the current hypothesis is that a switch to aerobic glycolysis in cafs would generate lactate and ketones , which , when secrete into the intracellular space , act as paracrine oncometabolites to fuel oxidative mitochondrial metabolism in tumor cells .
the metabolic switch to aerobic glycolysis , referred to as the  reverse warburg effect 
( fig .  1 ) , occurs in cafs through molecular mechanisms that are largely undefined . a recent paper by zhang et  al
. showed that downregulation of isocitrate dehydrogenase 3 ( idh3 ) plays a critical role in the metabolic reprogramming of cafs .
downregulation of idh3 decreases the effective level of -ketoglutaric acid ( -kg ) by reducing the ratio of -kg to fumurate and succinate ; this results in inhibition of prolyl hydroxylase domain - containing protein 2 ( phd2 ) and stabilization of hypoxia - inducible factor 1- ( hif1 ) protein .
the accumulation of hif1 , in turn , promotes glycolysis by increasing the uptake of glucose , upregulating expression of glycolytic enzymes under normoxic conditions , and inhibits oxidative phosphorylation by upregulating nadh dehydrogenase 1  subcomplex 4-like 2 ( ndufa4l2 ) .
cafs from tumor samples exhibit low levels of idh3 , and overexpression of idh3 prevents transformation of fibroblasts into cafs .
together , these findings reveal that idh3 is a critical metabolic switch in cafs . 

this includes metabolic reprogramming in cafs . in triple - negative breast cancer ( bc ) , tumor cells are prone to glycolysis and the adjacent cafs can also adapt to glycolysis . the acidic environment generated by this not only activates matrix metalloproteinase ( mmp ) , but also prevents attack from immune cells .
however , in the luminal subtype of breast cancer , tumor cells are not prone to glycolysis although their adjacent cafs can adopt glycolysis .
metabolic intermediates , such as lactate , secreted by cafs can be utilized by tumor cells for the biosynthesis of macromolecules .
the metabolic symbiosis between tumor cells and cafs provides a growth advance for the proliferation and metastatic dissemination of tumor cells . 
 
this includes metabolic reprogramming in cafs . in triple - negative breast cancer ( bc ) ,
tumor cells are prone to glycolysis and the adjacent cafs can also adapt to glycolysis . the acidic environment generated by this not only activates matrix metalloproteinase ( mmp ) , but also prevents attack from immune cells .
however , in the luminal subtype of breast cancer , tumor cells are not prone to glycolysis although their adjacent cafs can adopt glycolysis .
metabolic intermediates , such as lactate , secreted by cafs can be utilized by tumor cells for the biosynthesis of macromolecules .
the metabolic symbiosis between tumor cells and cafs provides a growth advance for the proliferation and metastatic dissemination of tumor cells .
first , cafs promote a dynamic metabolic interaction with tumor cells and generate a metabolic niche to nourish tumor growth .
an example is breast cancer , a heterogeneous disease that can be divided into at least 4 different subtypes based on gene expression profiling : luminal a , luminal b , human epidermal growth factor receptor 2 ( her2 ) , and basal - like .
after examining markers of glycolysis , autophagy , and proliferation in 740 tumor tissues , choi et  al . identified 4 different metabolic phenotypes in tumor and stroma .
these include warburg type ( glycolysis in tumor cells , non - glycolysis in stroma ) , reverse warburg type ( non - glycolysis in tumor cells , glycolysis in stroma ) , mixed type ( glycolysis in both tumor cells and stroma ) , and null type ( non - glycolysis in both tumor cells and stroma ) ( fig .  1 ) .
triple - negative ( basal - like ) breast cancer is enriched in mixed and warburg types with high metabolic activity , whereas luminal breast cancer is enriched in null and reverse warburg types with low metabolic activity .
this study reveals the metabolic heterogeneity in breast cancer , and demonstrates a correlation between tumor subtypes and metabolic phenotypes .
new therapeutic approaches that metabolically uncouple the  symbiosis  between tumor cells and cafs may inhibit the development and growth of tumors .
second , tumor cells co - evolve with nafs during tumor progression and reprogram them into cafs .
once reprogrammed , the caf phenotype becomes  permanent  even in the absence of continued exposure to intratumoral stimuli .
this stable phenotype suggests that epigenetic regulation and an autocrine signaling loop operate in the reprogramming of cafs .
identification of the mechanisms that govern these inferred processes may provide a new approach to target cafs .
fuel source  enabling tumor cell propagation , survival , and systemic dissemination , they are a heterogeneous cell population .
several cell types can be transdifferentiated into cafs ; the majority of cafs are derived from resident tissue fibroblasts and mesenchymal stem cells .
stellate cells are predominantly responsible for the desmoplastic reaction seen in chronic pancreatitis and pancreatic cancer , as well as in liver fibrosis , and are categorized as cafs when present in cancer tissue .
in addition , epithelial and endothelial cells can be converted to cafs through epithelial - mesenchymal transition and endothelial - mesenchymal transition , respectively .
thus , cafs may be derived from multiple tissue types , reflecting local and distant cues that are sensed during tumorigenesis , and thus can not be referred to as a single population of cells .
although many exciting studies have been completed , the remaining challenge is to translate our knowledge into targeting tumor cells to alleviate side effects , drug resistance , metastasis , and recurrence .
we apologize to the many contributors to this field whose work is important but could not be cited due to space limitations . our study is supported by the grants from nih ( ro1s ca125454 and ca188118 ) , dod breakthrough award ( bc140733p1 ) , the mary kay ash foundation ( to b. p. zhou ) , and the national natural science foundation of china ( 81402432 to j. liu ) .
 abstractcancer - associated fibroblasts ( cafs ) are major participants in the crosstalk between tumor cells and their microenvironment . 
 cafs provide not only multiple soluble factors but also metabolic fuels to promote tumor growth , invasion , and metastasis . 
 we discuss recent developments delineating the effects of metabolic symbiosis between cafs and tumor cells on tumor growth . 
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Acknowledgments