Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance

Abstract

Prostate cancer is characterized by a high degree of heterogeneity, which poses a major challenge to precision therapy and drug development. In this review, we discuss how nongenetic factors contribute to heterogeneity of prostate cancer. We also discuss tumor heterogeneity and phenotypic switching related to anticancer therapies. Lastly, we summarize the challenges targeting the tumor environments, and emphasize that continued exploration of tumor heterogeneity is needed in order to offer a personalized therapy for advanced prostate cancer patients.

Fig. 1. Intratumor and intertumor heterogeneity of prostate cancer.

Whole-mount cross-section of a radical prostatectomy specimen has two separated tumor foci. One focus is in the right anterior of the prostate (Gleason score 4 + 3 = 7, Group 3) whereas another focus is in the left posterior of the prostate (Gleason score 5 + 4 = 9, Group 5). Scale bars, 4 mm (left) and 100 µm (right). Methods: Radical prostatectomy specimens were serially sectioned into 3 mm slices and completely embedded. The case was reviewed by a single urologic pathologist (R.G.) in 2021. The following features were monitored: Gleason Score and Grade Group according to the International Society of Urological Pathology (ISUP) 2014 guidelines. The percentages of Gleason pattern 3, 4, and 5 were estimated, including presence of tertiary Gleason patterns.

Fig. 2. The heterogenous tumor microenvironment.

The tumor microenvironment possesses a dynamic topography within the tumor and is composed of cancer-associated fibroblasts, stromal cells, extracellular matrix, and immune cells. Hypoxic status, vasculature, and epigenetics, all may have a complex crosstalk with prostate cancer cells in dynamic ways.

Fig. 3. Therapy-mediated tumor heterogeneity.

Primary tumors are composed of different subclones. Some subclones are sensitive to selective pressures, including chemotherapy, androgen deprivation therapy, or immunotherapy, while some subclones are resistant to anticancer therapies. Outgrowth of resistant subclones, phenotype switch, or emergence of a new tumor phenotype are strongly related for resistance to anticancer therapies. As a result, the tumor heterogeneity plays a fundamental role in cancer progression to metastasis.