High levels of acute phase proteins and soluble 70 kDa heat shock proteins are independent and additive risk factors for mortality in colorectal cancer

Abstract

Recently, we reported that high soluble Hsp70 (sHsp70) level was a significant predictor of mortality during an almost 3-year-long follow-up period in patients with colorectal cancer. This association was the strongest in the group of <70-year-old female patients as well as in those who were in a less advanced stage of the disease at baseline. According to these observations, measurement of the serum level of sHsp70 is a useful, stage-independent prognostic marker in colorectal cancer, especially in patients without distant metastasis. Since many literature data indicated that measurement of C-reactive protein (CRP) and other acute phase proteins (APPs) may also be suitable for predicting the mortality of patients with colorectal cancer, it seemed reasonable to study whether the effect of sHsp70 and other APPs are related or independent. In order to answer this question, we measured the concentrations of CRP as well as of other complement-related APPs (C1 inhibitor, C3, and C9) along with that of the MASP-2 complement component in the sera of 175 patients with colorectal cancer and known levels of sHsp70, which have been used in our previous study. High (above median) levels of CRP, C1 esterase inhibitor (C1-INH), and sHsp70 were found to be independently associated with poor patient survival, whereas no such association was observed with the other proteins tested. According to the adjusted Cox proportional hazards analysis, the additive effect of high sHsp70, CRP, and C1-INH levels on the survival of patients exceeded that of high sHsp70 alone, with a hazard ratio (HR) of 2.83 (1.13-70.9). In some subgroups of patients, such as in females [HR 4.80 (1.07-21.60)] or in ≤70-year-old patients [HR 11.53 (2.78-47.70)], even greater differences were obtained. These findings indicate that the clinical mortality-prediction value of combined measurements of sHsp70, CRP, and C1-INH with inexpensive methods can be very high, especially in specific subgroups of patients with colorectal cancer.

Fig. 1

Survival of patients with combinations of high and low (see Table 1) levels of CRP, C1-INH, and sHsp70 serum concentrations. 0 Neither is high, 1 only sHsp70 is high, 3 all three are high. Hazard ratio: Cox regression analysis adjusted to sex and age for the comparison of combinations 3 vs. 1 is indicated

Fig. 2

Survival of male vs. female patients (upper row), as well as of patients aged less than or equal to 70 years of age or older than 70 years (lower row), with high and low (see Table 1) levels of CRP, C1-INH, and sHsp70 serum concentrations. 0 Neither is high, 1 only sol Hsp70 is high, 3 all three are high. Results of Cox regression analysis adjusted to sex or age for the comparison of combinations 3 vs. 1 are indicated