Perivascular Cell Status is Associated with Survival in Metastatic Colorectal Cancer

Artur Mezheyeuski ^1,2 Tormod Kyrre Guren ^4,5 Ina Hrynchyk ¹⁴ Maja Bradic Lindh ¹ David Edler ³ Anca Dragomir ⁶ Per Pfeiffer ⁷ Elin H. Kure ⁸ Tone Ikdahl ⁹ Eva Skovlund ¹⁰ Kristian Pietras ¹¹ Fredrik Ponten ⁶ Jan Mulder ¹² Marja Hallström ¹ Camilla Qvortrup ⁷ Katarina Öhrling ¹ Anna Portyanko ² Kjell Magne Tveit ⁴ Peter Ragnhammar ¹ Bengt Glimelius ⁶ Halfdan Sorbye ¹³ Arne Östman ¹

¹Oncology-Pathology, Karolinska Institutet, Sweden
²Department of Pathology, Belarusian State Medical University, Belarus
³Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, Sweden
⁴Department of Oncology-Pathology, Oslo University Hospital, Norway
⁵K.G.Jebsen Colorectal Cancer Research Center, Oslo University Hospital, Norway
⁶Department of Immunology, Genetics and Pathology, Uppsala University, Sweden
⁷Department of Oncology-Pathology, University of Southern Denmark, Denmark
⁸Department of Cancer Genetics, Institute for Cancer Research, Norway
⁹Akershus University Hospital, Akershus University Hospital, Norway
¹⁰School of Pharmacy, University of Oslo and the Norwegian Institute of Public Health, Norway
¹¹Division of Translational Cancer Research, Lund University, Sweden
¹²Department of Neuroscience, Science for Life Laboratory, Karolinska Institutet, Sweden
¹³Department of Oncology-Pathology, Haukeland University Hospital, Norway
¹⁴Department of General Pathology #2, State Clinical Bureau of Pathology, Minsk, Belarus

Background: Perivascular cells (PC) regulate multiple aspects of tumor biology. PC status in larger series of clinical samples remains poorly characterized. The role of PC as predictors of survival or response to the therapy in colorectal cancer has not been analyzed. This study investigates the variation in PC status and the prognostic and response-predictive significance of PC markers and vessel characteristics in colon cancer (CC) and metastatic colorectal cancer (mCRC).

Methods: Tumor sections of CC from a randomized phase-III trial of adjuvant treatment and tissue microarrays with primary tumors from two independent cohorts of mCRC were subjected to 2-4 double-staining with endothelial marker (CD34) and one of pericyte markers: platelet-derived growth factor receptor-alpha and -beta (PDGFR-α, PDGFR-β), smooth muscle α-actin (ASMA) and desmin. A novel dedicated methodological pipeline for digital image-analyses was used to quantitate characteristics of vessels and PC.

Results: Analyses of associations of vascular characteristics uncovered previously un-recognized independent expression of the analyzed perivascular markers.

Concerning prognostic relevance, we observed significant associations between perivascular PDGFR-β status and DFS in CC, and between perivascular PDGFR-α or PDGFR-β and survival in metastatic disease in mCRC.

The associations between survival endpoints and perivascular PDGFR-β were stronger in the treatment group of the adjuvant study suggesting impact on response to treatment. Explorative analyses of the population-based mCRC cohort indicated reduced benefit of bevacizumab-treatment in the group of cases with low perivascular PDGFR-β expression.

Conclusion: Perivascular PDGFR-α and -β in primary tumors are novel independent markers predicting survival in metastatic CRC. Analyses also imply novel relationships between PC and response to treatment. Collectively, the results imply previously un-recognized potential of PC as candidate biomarkers and targets for therapy.