Expression of the hyaluronan-mediated motility receptor RHAMM in tumor budding cells identifies aggressive colorectal cancers.
Expression of the hyaluronan-mediated motility receptor (RHAMM, CD168) predicts adverse clinicopathological features and decreased survival for colorectal cancer (CRC) patients. Using full tissue sections, we investigated the expression of RHAMM in tumor budding cells of 103 primary CRCs to characterize the biological processes driving single-cell invasion and early metastatic dissemination. RHAMM expression in tumor buds was analyzed with clinicopathological data, molecular features and survival. Tumor budding cells at the invasive front of CRC expressed RHAMM in 68% of cases. Detection of RHAMM-positive tumor budding cells was significantly associated with poor survival outcome (P = .0312), independent of TNM stage and adjuvant therapy in multivariate analysis (P = .0201). RHAMM-positive tumor buds were associated with frequent lymphatic invasion (P = .0007), higher tumor grade (P = .0296), and nodal metastasis (P = .0364). Importantly, the prognostic impact of RHAMM expression in tumor buds was maintained independently of the number of tumor buds found in an individual case (P = .0246). No impact of KRAS/BRAF mutation, mismatch repair deficiency and CpG island methylation was observed. RHAMM expression identifies an aggressive subpopulation of tumor budding cells and is an independent adverse prognostic factor for CRC patients. These data support ongoing efforts to develop RHAMM as a target for precision therapy.
Translational Research Unit (TRU), Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland. Electronic address: viktor.koelzer@pathology.unibe.ch.
Viktor Hendrik
VH
Koelzer
Institute of Pathology, University of Basel, CH-4031 Basel, Switzerland.
Bettina
B
Huber
Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, University of Basel, CH-4031 Basel, Switzerland.
Valentina
V
Mele
Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, University of Basel, CH-4031 Basel, Switzerland.
Giandomenica
G
Iezzi
Translational Research Unit (TRU), Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland.
Mafalda
M
Trippel
Translational Research Unit (TRU), Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland.
Eva
E
Karamitopoulou
Clinical Pathology Division, Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland.
Inti
I
Zlobec
Translational Research Unit (TRU), Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland.
Alessandro
A
Lugli
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor
CD168; Colorectal cancer; Hyaluronan-mediated motility receptor; Prognostic factor; RHAMM; Tumor budding