Clinical Impact of Hyaluronan Accumulation in the Tumor Microenvironment

Hyaluronan accumulation correlates with poor outcomes

Elevated hyaluronan (HA) levels in the tumor microenvironment serve as an indicator for poor survival in ovarian cancer, invasive breast cancer, prostate cancer, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), gastric cancer, and pancreatic cancer.1-10

HA staining was performed in research-based assays, with different methodology and cutoff thresholds in each tumor type.1,5-7,9,10 Clinical cutoff values have not been established.

Select from the icons below to learn about the clinical impact of HA accumulation in each cancer type.

Clinical impact of HA accumulation in the TME of pancreatic ductal adenocarcinoma (PDA)1

Determination of HA accumulation1

HA-high: stain intensity of ≥ 113 (on a scale of 0-300)

HA-low: stain intensity of ≤ 112

Whatcott et al. HA deposition and collagen deposition were analyzed in a cohort of biopsy sections from 50 patients with PDA. HA was measured in a research-based, biotinylated HA-binding protein assay scored by digital image analysis. Quantitative analysis was performed by multiplying stain area by intensity for a maximum score of 300. Samples were categorized as having low levels of HA if scores were 112 or less and high levels of HA if scores were 113 or greater. Clinical investigation and validation of HA as a predictive biomarker and prognostic tool are in progress.

HA accumulation correlated with significantly worse outcomes, with median survival of 9.3 months for HA-high patients compared with 24.3 months for HA-low patients (P = 0.037).1

Clinical impact of stromal HA accumulation in ovarian cancer7

Determination of HA accumulation7

HA-low, HA-moderate, and HA-high designations were determined by two observers blinded to the clinical outcome. Disagreement occurred on less than 10% of the slides, with consensus being reached upon further discussion.

Anttila et al. Overall survival (OS) according to stromal HA levels (low, n = 93; moderate, n = 115; high, n = 91). Recurrence-free survival (RFS) according to stromal HA levels (low, n = 59; moderate, n = 62; high, n = 42). Dotted vertical line shows overall comparison at 5 years. HA was measured in a research-based, biotinylated HA-binding protein assay scored by two observers blinded to the clinical data, with an arbitrary cutoff to define HA-high staining. Clinical investigation and validation of HA as a predictive biomarker and prognostic tool are in progress.

HA accumulation correlated with significantly reduced OS (P = 0.002) and increased likelihood of recurrence (P = 0.008) in ovarian cancer patients.7

Clinical impact of stromal HA accumulation in breast cancer9

Determination of HA accumulation9

HA-weak: no intense HA signal in the peritumoral stroma

HA-moderate: < 50% with intense signal

HA-strong: ≥ 50% with intense signal

Designations were determined by two observers.

Auvinen et al. OS according to stromal HA levels (weak, n = 7; moderate, n = 56; strong, n = 80). HA was measured in a research-based, biotinylated HA-binding protein assay scored by two observers, with an arbitrary cutoff of ≥ 50% defined as strong HA-positive stain. Clinical investigation and validation of HA as a predictive biomarker and prognostic tool are in progress.

Five-year OS significantly correlates with HA-staining intensity in the stromal compartment of invasive breast cancer (P = 0.0001).9

Clinical impact of stromal HA accumulation in prostate cancer10

Determination of HA accumulation10

HA-low: low level of strongly stained stroma (≤ 15%)

HA-high: high level of strongly stained stroma (> 15%)

Lipponen et al. OS according to stromal HA levels (low [≤ 15%], n = 83; high [> 15%], n = 83). HA was measured in a research-based, biotinylated HA-binding protein assay scored by an observer, with an arbitrary cutoff of > 15% defined as HA-high staining. Clinical investigation and validation of HA as a predictive biomarker and prognostic tool are in progress.

Elevated levels of stromal HA staining (> 15% of tissue section) were significantly associated with worse outcomes in prostate cancer (P = 0.003).10

Clinical impact of stromal HA accumulation in CRC6

Determination of HA accumulation6

HA-negative: HA signal was absent

HA-weak: weak signal intensity

HA-moderate: moderate signal intensity

HA-strong: strong signal intensity

Designations were determined by two observers blinded to the clinical data.

Ropponen et al. OS according to stromal HA levels (negative staining, n = 70; weak staining, n = 14; moderate staining, n = 67; strong staining, n = 36). HA was measured in a research-based, biotinylated HA-binding protein assay scored by two observers blinded to the clinical data, with an arbitrary cutoff to define HA-strong staining. Clinical investigation and validation of HA as a predictive biomarker and prognostic tool are in progress.

HA staining intensity in CRC correlated with OS. Sixty percent of patients with low levels of HA (≤ 25%) survived 14 years, whereas 30% of patients with HA accumulation (≥ 75%) survived 12 years.6

Clinical impact of HA accumulation in gastric cancer5

Determination of HA accumulation5

HA-negative: all tumor cells negative

≥ 30% HA-positive: ≥ 30% of tumor cells with positive staining

< 30% HA-positive: < 30% of tumor cells with positive staining

Estimations were determined by a pathologist blinded to the clinical data.

Setälä et al. OS according to fraction of HA-positive tumor cells (negative, n = 15; low [< 30% positive], n = 105; high [≥ 30% positive], n = 95). HA was measured in a research-based, biotinylated HA-binding protein assay scored by a pathologist blinded to the clinical data, with an arbitrary cutoff of ≥ 30% of HA-positive tumor cells. Clinical investigation and validation of HA as a predictive biomarker and prognostic tool are in progress.

Patients with gastric cancer with a greater proportion of HA-positive tumor cells had worse survival (P = 0.0025) than those with less HA.5