ID
37
Cancer Name
Kidney Cancer (Renal Papillary Carcinoma)
Main Grouping
Urinary
Organ System
Kidneys
Cell Origin
Epithelial (renal papillary)
Pathways Affected
Papillary renal cell carcinoma involves two molecularly distinct pathway dysregulation profiles based on type, with MET/MAPK/ERK/PI3K/AKT/mTOR constitutive activation as the Type 1 pRCC dominant axis and chromatin modifier pathway disruption (SETD2/BAP1/PBRM1) complemented by Hippo signaling loss and CIMP epigenetic silencing as the dominant Type 2 pRCC axes.
The MET/MAPK/ERK pathway is constitutively activated in approximately 81 percent of Type 1 pRCC through MET kinase domain point mutations, copy number gains of chromosome 7q31 amplifying MET, and TFE3 gene fusions that drive MET transcriptional upregulation; constitutive MET/HGF receptor kinase activity drives downstream MAPK/ERK proliferative signaling and PI3K/AKT/mTOR cell survival and metabolic signaling; curcumin, quercetin, and EGCG all inhibit MET downstream MAPK/ERK and PI3K/AKT signaling in RCC-relevant cell models.
The PI3K/AKT/mTOR pathway is activated downstream of MET in Type 1 pRCC and through PTEN loss and NF2/Hippo signaling disruption in Type 2 pRCC; mTORC1 drives protein synthesis, metabolic reprogramming, and cellular anabolism in pRCC cells; the NF2 tumor suppressor gene at chromosome 22q12 encodes merlin, a regulator of the Hippo kinase cascade that also suppresses mTORC1 through inhibiting TORC1-activating kinases; NF2 mutations in approximately 10 percent of Type 2 pRCC directly activate mTORC1; curcumin induces apoptosis and autophagy in ACHN RCC cells through AKT/mTOR suppression with significant reduction of AKT/mTOR protein expression confirmed by western blot and immunofluorescence in vitro and in vivo xenograft tumor growth inhibition (PMC8806675). The chromatin modifier pathway is disrupted in Type 2 pRCC through SETD2 loss-of-function mutations eliminating H3K36me3 histone methylation, BAP1 loss disrupting histone H2A ubiquitylation and chromatin structure, and PBRM1 loss disrupting SWI/SNF ATP-dependent chromatin remodeling; SETD2, BAP1, and PBRM1 are key histone and chromatin regulators directly relevant to epigenetic dietary phytochemical interventions; sulforaphane and curcumin inhibit HDAC and DNMT activities targeting chromatin remodeling pathways. The CIMP epigenetic silencing pathway is the most aggressive molecular subset of pRCC, with universal CDKN2A promoter hypermethylation silencing p16 CDK4/6 inhibitor function and driving G1/S cell cycle entry unchecked; EGCG, sulforaphane, and curcumin inhibit DNMT activity potentially targeting CIMP-associated promoter methylation. The Hippo signaling pathway is disrupted through NF2 loss-of-function mutations in approximately 10 percent of Type 2 pRCC, releasing YAP/TAZ transcriptional co-activators from LATS1/2 kinase-mediated inhibition; YAP/TAZ drive proliferative gene programs including cyclin D1 and CTGF; quercetin and curcumin inhibit YAP/TAZ transcriptional activity in cancer cell models. The Nrf2 antioxidant response pathway is constitutively activated through NFE2L2 gain-of-function mutations in pRCC, driving antioxidant gene expression, glutathione biosynthesis, and drug resistance in a subset of pRCC; dietary Nrf2-activating phytochemicals including sulforaphane and curcumin also activate Nrf2 in normal kidney cells, providing differential protection. The p53 tumor suppressor pathway is disrupted through TP53 mutations in a subset of pRCC, particularly Type 2; curcumin and quercetin restore p53-dependent apoptosis in RCC cell models. The VEGF angiogenesis pathway is active in pRCC through HIF-1alpha upregulation driven by MET/PI3K/AKT signaling and FH loss-induced fumarate accumulation epigenetically activating VEGF expression in HLRCC.
Description
Papillary renal cell carcinoma (pRCC) is the second most common histological subtype of renal cell carcinoma, accounting for approximately 15 to 20 percent of all RCC cases, which in turn collectively account for approximately 90 percent of all kidney malignancies. Kidney cancer overall is estimated to have approximately 81,610 new cases and 14,390 deaths in the United States in 2024. pRCC affects men approximately 2 to 3 times more frequently than women, and peaks in the sixth to seventh decades of life. The 5-year overall survival for localized pRCC (stage I-II) is approximately 80 to 90 percent, for regional pRCC approximately 50 to 65 percent, and for metastatic pRCC approximately 10 to 20 percent, with a median overall survival of approximately 12 to 15 months for advanced disease.
pRCC is divided into two distinct histological and molecular subtypes. Type 1 pRCC is predominantly a lower-grade tumor driven by MET oncogene pathway alterations in approximately 81 percent of cases; the MET proto-oncogene at chromosome 7q31 encodes the HGF (hepatocyte growth factor) receptor tyrosine kinase, and MET pathway constitutive activation drives MAPK/ERK and PI3K/AKT/mTOR proliferative and survival signaling in Type 1 pRCC; chromosomal gains of chromosome 7 (carrying MET) and chromosome 17 (carrying TP53) are characteristic of Type 1 pRCC. Type 2 pRCC is a molecularly heterogeneous group with worse prognosis, driven primarily by chromatin modifier gene mutations in SETD2 (H3K36 methyltransferase), BAP1 (deubiquitylase), and PBRM1 (SWI/SNF chromatin remodeling complex), along with NF2 loss disrupting Hippo signaling, CDKN2A loss, and TP53 mutations; a subset of Type 2 pRCC (subgroup C2c) shows a renal-specific CpG island methylator phenotype (CIMP) with universal CDKN2A promoter hypermethylation and carries the worst prognosis among pRCC subtypes.
The TCGA comprehensive molecular characterization of pRCC (PMC4775252, published in the New England Journal of Medicine in 2016) documented key pathway alterations: SWI/SNF complex mutations in 19.7 percent of Type 1 and 26.7 percent of Type 2 tumors; chromatin modifier pathway mutations in 35.2 percent and 38.3 percent respectively; Hippo signaling pathway mutations in 2.8 percent and 10.0 percent respectively; and TFE3/TFEB gene fusions in 10.6 percent of all pRCC tumors. NFE2L2 (NRF2) activating mutations are found in pRCC, making Nrf2 pathway biology directly relevant.
Multiple plant phytochemicals have documented activity in RCC cell line models. A comprehensive review (PMC5796057) documented that curcumin, EGCG, quercetin, and resveratrol all have preclinical anti-RCC activity through AKT/mTOR suppression, apoptosis induction, and autophagy activation relevant to both the PI3K/AKT/mTOR pathway constitutively activated through MET signaling in Type 1 pRCC and PTEN alterations in Type 2 pRCC. Curcumin in ACHN RCC cells induced apoptosis and autophagy through AKT/mTOR suppression, with in vivo xenograft tumor growth inhibition confirmed (PMC8806675).
Plant-Based Description
Whole-food plant-based dietary patterns provide nutrients and phytochemicals with documented activity relevant to papillary renal cell carcinoma through direct RCC cell line anti-proliferative activity, MET downstream MAPK/ERK and PI3K/AKT/mTOR inhibition targeting the dominant Type 1 pRCC oncogenic driver, AKT/mTOR suppression with apoptosis and autophagy induction in RCC cell models and in vivo xenograft tumor growth inhibition, chromatin modifier pathway-targeted HDAC and DNMT inhibition relevant to SETD2/BAP1/PBRM1-disrupted Type 2 pRCC, Nrf2 antioxidant activation in renal tubular cells, VEGF angiogenesis suppression, and cell cycle arrest restoring CDKN2A pathway function. Curcumin from turmeric has the most directly documented AKT/mTOR suppression evidence in RCC cells: curcumin induced apoptosis and autophagy in ACHN RCC cells through AKT/mTOR suppression confirmed by western blot and immunofluorescence, significantly inhibited tumor size and weight in xenograft models, and reduced IL-6, IL-8, and TNF-alpha inflammatory cytokines (PMC8806675). A comprehensive review (PMC5796057) documented curcumin, EGCG, quercetin, and resveratrol as the leading natural compounds with preclinical anti-RCC activity through multiple mechanisms. EGCG from green tea inhibits MET, VEGF, and PI3K/AKT/mTOR signaling. Quercetin inhibits AKT/mTOR and promotes apoptosis in RCC-relevant models. Sulforaphane activates Nrf2 and inhibits HDAC activity in renal cell models. Beta-carotene and vitamin C from fruits and vegetables provide antioxidant protection in renal tubular cells where pRCC arises.
Plant Chemistry Detail
Curcumin from turmeric has the most directly documented anti-RCC evidence with in vitro and in vivo validation. A study published in Bioengineered (PMC8806675) documented curcumin in ACHN renal cell carcinoma cells: curcumin significantly inhibited cell viability in a dose-dependent manner; significantly increased apoptosis confirmed by Annexin V-FITC/PI flow cytometry; significantly reduced AKT/mTOR protein expression (AKT and mTOR pathway proteins) confirmed by western blot and immunofluorescence; significantly elevated autophagy-related proteins LC3B and Beclin-1; significantly reduced IL-6, IL-8, and TNF-alpha inflammatory cytokine levels by ELISA; and in C57BL/6 nude mouse xenograft experiments significantly inhibited tumor size, weight, and volume compared to controls; the mechanistic analysis confirmed that curcumin-induced apoptosis was significantly reversed by 3-MA (autophagy inhibitor), confirming that autophagy was required for curcumin-mediated cell death in RCC cells; this establishes that curcumin targets the AKT/mTOR pathway constitutively activated through MET signaling in Type 1 pRCC and PTEN/NF2 alterations in Type 2 pRCC.
A comprehensive review (PMC5796057) documented the anti-RCC activity of multiple plant phytochemicals: curcumin dephosphorylated AKT and downregulated BCL-2, BCL-XL, and IAP proteins while activating caspase-3 and cytochrome C release in RCC cells; curcumin also induced G1-phase cell cycle arrest through CDK4/6 inhibition and G2/M arrest in other RCC cell lines directly targeting the CDKN2A-CDK4/6-RB pathway dysregulated through CIMP in the C2c pRCC subgroup; EGCG inhibited RCC cell proliferation through VEGF suppression and MET/PI3K/AKT pathway inhibition relevant to MET-driven Type 1 pRCC; quercetin inhibited AKT phosphorylation and mTOR signaling, promoted PARP cleavage, induced G1 cell cycle arrest, and reduced IL-6, IL-10, and STAT3 activation in RCC-relevant models; resveratrol inhibited mTOR and VEGF in RCC models.
A transcriptomics study specifically in papillary RCC (KIRP, PMC12249829) documented curcumin's effects in the papillary RCC molecular context: curcumin combined therapy showed enhanced apoptosis through p53 activation and caspase-3 cleavage, activated YAP (Yes-Associated Protein) relevant to the Hippo signaling pathway disrupted through NF2 mutations in approximately 10 percent of Type 2 pRCC, and addressed DNMT3A-DNA methylation pathway alterations specific to KIRP where DNMT3A promotes tumor cell proliferation by silencing tumor suppressor genes. Sulforaphane from cruciferous vegetables activates Nrf2/ARE antioxidant response in renal tubular cells, providing protection against oxidative damage in the proximal tubule cells that are the cell of origin for pRCC; sulforaphane additionally inhibits HDAC activity targeting the chromatin remodeling pathway disrupted by SETD2, BAP1, and PBRM1 mutations in Type 2 pRCC. Ellagic acid from pomegranate inhibits PI3K/AKT and MET downstream kinase signaling in kidney cancer cell models. Allicin and diallyl compounds from garlic inhibit NF-kB and AKT signaling in RCC models.
Nutritional Focus
Nutritional focus in papillary renal cell carcinoma research is led by curcumin from turmeric, with the most directly documented anti-RCC AKT/mTOR evidence from a published Bioengineered study (PMC8806675) in ACHN renal cell carcinoma cells documenting significant cell viability inhibition, significantly increased apoptosis by flow cytometry, significantly reduced AKT and mTOR protein expression by western blot and immunofluorescence, significantly elevated autophagy proteins LC3B and Beclin-1, reduced inflammatory cytokines IL-6, IL-8, and TNF-alpha by ELISA, and significant in vivo inhibition of xenograft tumor size, weight, and volume — directly targeting the AKT/mTOR pathway constitutively activated through MET kinase mutations and chromosome 7 gains in approximately 81 percent of Type 1 pRCC; a comprehensive natural compounds in RCC review (PMC5796057) documenting curcumin, EGCG, quercetin, and resveratrol as having the broadest preclinical anti-RCC evidence through AKT/mTOR suppression, BCL-2/BCL-XL/IAP downregulation, caspase-3 and cytochrome C activation, and cell cycle arrest relevant to pRCC molecular targets; EGCG from green tea inhibiting MET downstream VEGF and PI3K/AKT signaling relevant to MET-driven Type 1 pRCC; quercetin inhibiting AKT phosphorylation, mTOR, STAT3, and VEGF in RCC cell models; sulforaphane from cruciferous vegetables activating Nrf2/ARE in renal proximal tubule cells and inhibiting HDAC activity targeting the chromatin remodeling pathway disrupted by SETD2, BAP1, and PBRM1 mutations in Type 2 pRCC; curcumin transcriptomics specifically in papillary RCC context (KIRP) documenting activation of YAP/Hippo signaling and DNMT3A-DNA methylation pathway targeting (PMC12249829) directly relevant to NF2-mutant Hippo signaling disruption in Type 2 pRCC and CIMP epigenetic silencing in the C2c aggressive pRCC subgroup.
Research Notes
pRCC epidemiology: 2nd most common RCC histology, approximately 15-20% of all RCC; kidney cancer overall approximately 81,610 new cases and 14,390 deaths in United States 2024; male:female approximately 2-3:1; peak incidence 6th-7th decade; 5-year survival localized approximately 80-90%, regional approximately 50-65%, metastatic approximately 10-20%. TCGA pRCC (PMC4775252, NEJM 2016): 161 pRCC tumors — Type 1 (75), Type 2 (60), NOS (26); Type 1: MET pathway alterations 81%; chromosome 7 and 17 gains; SWI/SNF mutations 19.7%; chromatin modifier mutations 35.2%; Hippo mutations 2.8%; Type 2: SETD2, BAP1, PBRM1 chromatin modifier mutations 38.3%; NF2 Hippo pathway mutations 10.0%; CDKN2A CIMP universal hypermethylation in subgroup C2c; TFE3/TFEB gene fusions 10.6% overall; NFE2L2/NRF2 activating mutations present.
Curcumin AKT/mTOR in RCC (PMC8806675): ACHN cells; dose-dependent viability inhibition; apoptosis increased by Annexin V flow cytometry; AKT and mTOR protein expression significantly reduced by western blot and immunofluorescence; autophagy proteins LC3B and Beclin-1 elevated; IL-6, IL-8, TNF-alpha reduced; xenograft tumor size/weight/volume significantly inhibited; 3-MA inhibitor experiments confirmed autophagy required for curcumin-induced cell death. Curcumin and natural compounds in RCC review (PMC5796057): EGCG, curcumin, resveratrol, quercetin with documented RCC preclinical activity through PI3K/AKT/mTOR, BCL-2 downregulation, caspase-3 activation. Curcumin in KIRP transcriptomics (PMC12249829): YAP/Hippo pathway activation, DNMT3A-DNA methylation pathway targeting directly relevant to papillary RCC.
Notes Visibility
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Key Foods
Turmeric,Broccoli,Kale,Spinach,Brussels Sprouts,Cauliflower,Garlic,Yellow Onion,Carrot,Tomato,Sweet Potato,Apple,Blueberry,Pomegranate,Grape,Raspberry,Cranberry,Orange,Lemon,Soybeans,Edamame,Green Lentils,Black Beans,Chickpeas,Brown Rice,Quinoa,Oats,Wild Rice,Rye Berries,Sorghum,Walnut,Almond,Brazil Nut,Pumpkin Seeds,Flaxseed,Chia Seeds,Sesame Seeds,Hemp Seeds,Shiitake,Maitake,Cremini,Portobello,Lions Mane,Green Tea,Ginger,Black Pepper,Garlic Powder,Parsley,Rosemary,Oregano, Leek,Avocado,Artichoke,Radish,Tangerine, Red Onion
Linked Nutrients
vitamin-c,vitamin-e,vitamin-d3,vitamin-b9,vitamin-b6,vitamin-a,selenium,zinc,magnesium,calcium,potassium,iron,curcumin,quercetin,egcg,sulforaphane,resveratrol,ellagic-acid,beta-carotene,anthocyanins,beta-glucans,dietary-fiber,plant-ala-omega3
