Human Prostrate Cancer Hallmarks Map

Concept of Human Prostrate Cancer Hallmarks Map (HPCHM)

Illustration

Human Prostate Cancer Hallmarks Map (HPCHM) aims to represent the detail molecular mechanisms of ten classic hallmarks (underlined) and three prostate cancer unique hallmarks (shown in red). Hallmark underlying cell biological and pathophenomic processes are indicated by white round rectangle and other important contributing factors are given as pale yellow rectangle.

Hallmark- Self-sufficiency in growth signaling: prostate cancer cells produce their own growth signals to trigger cell growth, proliferation and survival [4-7]

This hallmark indicates hyper-activation of growth factor mediated signaling due to overproduction of growth factors as a consequence of aucrine and paracrine production of growth factors and aberrant functioning of androgen receptor mediated signaling. Self-sufficiency in growth signaling is the central most driving force required for stimulation of prostate cancer cell proliferation, growth and survival. Most strikingly, these hallmark capability also significantly contribute in the acquisition of androgen independent phenotypes and consequent emergence of castration resistant prostate cancer.

Hallmark- Insensitivity to antigrowth signals: prostate cancer cells become unresponsive to growth restraining signals.[2,8,9]

This hallmark involves evasion of anti-growth and anti-proliferation associated signaling due to suppression of critical cell growth and cell proliferation associated negative regulators. The establishment of insensitivity to antigrowth signaling during the course of prostate tumorigenesis, is particularly achieved by inactivation of tumor suppressors (by various unfavorable circumstances such as deletion, mutation, loss of expression, rearrangement, promoter methylation and haplo-insufficiency) and deregulation of cell cycle. Insensitivity to antigrowth signaling or evasion of growth suppression critically promotes development of castration resistance.

Hallmark- Cell death resistance: prostate cancer cells resists and modulates apoptotic program [2,10-16]

This hallmark behaves as a critical pathophysiological factor for initiation and progression of majority of prostate adenocarcinomas. Inhibition or evasion of apoptosis is attained by the development of resistance to both intrinsic and extrinsic cell death programs and overall modulation of apoptotic program due to neutralization of death signal. Evasion of apoptosis significantly contributes for the acquisition of several cell biological and pathophenomic features including autophagy inhibition, anoikis resistance, chemo-resistance and radiation-resistance.Emergence of castration resistant prostate cancer is generally associated with an enhanced resistance to apoptosis.

Hallmark- Angiogenesis: prostate cancer cells trigger the formation of new blood vessels [2,17,18]

This hallmark indicates formation of new blood vessel and plays an obligatory role in promotion of prostate tumor growth as tumors cannot grow more than 2mm in size without oxygen and nutritional requirement. Actually, angiogenesis is needed for each and every step in prostate tumorigenesis, ranging from tumor outgrowth to its metastatic dissemination and the development of castration resistance. Angiogenesis is mediated by enhanced production of pro-angiogenic factors and suppression of angiogenesis associated switches.

Hallmark- Enabling Replicative Immortality: prostate cancer cells have unlimited replicative potential [2,19,20]

This hallmark essentially indicates the acquisition of unlimited replicative potential by the prostate cancer cells in order to promote macroscopic tumor formation. Telomere dysfunction along with reactivation of the telomerase reverse transcriptase activity (telomerase stabilization, which is typically associated with telomere maintenance) and downmodulation of replicative senescence program plays the major roles in imparting limitless replicative potential.

Hallmark- Metastasis: the ability of prostate tumor to escape from primary organ by evading the neighboring cells and disseminate to new sites

This hallmark characterizes the distant settlement of tumor cell and largely accounted for cancer associated cell death. The earliest step of prostate cancer metastasis is the local invasion which involves entry of cancer cells from the location of primary prostate tumor into the surrounding extracellular matrix and tumor associated stromal cell layer. But the patients with advanced metastatic castration resistant prostate cancer finally develop bone metastasis which is totally incurable. The development of prostate cancer metastasis mainly depends on the orchestration of various coordinated key cell biological features, namely as cell migration, invasion, cell adhesion, cell motility and epithelial mesenchymal transition.

Hallmark- Inflammation: promotion of prostate tumor through enhancement of inflammatory response [2,22]

This hallmark accelerates the aggressiveness of prostate tumorigenesis and its subsequent transformation into castration resistant metastatic pathological forms. For that purpose, an enhancement of inflammatory response is mediated by several factors, including growth factor mediated signaling, activation of inflammasome and associated signaling, over production of inflammatory mediators, stimulation of ROS(reactive oxygen species) driven responses. In addition, ROS induced oxidative stress triggers chronic or recurrent prostatic inflammation, which plays a crucial role in prostate tumorigenesis.

Hallmark- Metabolic Reprogramming: prostate cancer cells deregulate metabolic program and energetics to support tumor formation [2,23-25]

This hallmark crucially fuels for the disruption of normal metabolic regulation, leading to an enhancement of prostate tumorigenesis. Prostate cancer metabolic reprogramming is triggered by several crucial factors, comprising Warburg effect, reverse Warburg effect, cholesterol accumulation, mitochondrial biogenesis, intra-tumoral steroidogenesis, androgen receptor activation etc.

Hallmark- Avoidance of Immune Destruction: prostate cancer cells evade the monitoring capability of immune system [2,26,27]

This hallmark involves significant alterations in immune response during the course of prostate cancer progression. Avoidance of immune destruction is acquired due to an intense interplay of several pivotal factors including, inhibition of immune cell functioning, escape from immune surveillance, immuno-resistance, gaining of immune properties, immune-suppression and immune-modulation in the prostate tumor microenvironment etc.

Hallmark- Tumor Microenvironment: the surroundings of prostate tumor which critically fuels other hallmark manifestations [2,28,29]

This hallmark indicates prostate tumor surrounding ‘reactive stroma’ and plays the profound influential role in shaping the manifestations of other hallmark capabilities through various means, by supplying growth factors and matrix metalloproteases, inducing extracellular acidosis, triggering intra-tumoral hypoxia etc. Prostate tumor associated reactive ‘reactive stroma’ composed of various cell types including, cancer associated fibroblast (CAF), myofibroblast and adipocytes.

Prostate Cancer Unique Hallmark- Androgen Receptor (AR) mediated signaling: a nuclear receptor signaling axis that plays the most pivotal role in each and every steps of prostate tumorigenesis [2, 5-7]

This can be considered as prostate cancer unique hallmark that plays the most significant role in each and every step of prostate cancer initiation, development and corresponding castration resistance disease progression. This hallmark strongly modulates growth factor mediated signaling and there by stimulates self-sustenance in growth signaling [2, 5-7].

Prostate Cancer Unique Hallmark- Androgen Independence: prostate cancer cells develop a variety of mechanisms to survive and flourish in an androgen deprived environment [2, 5-7]

The emergence of androgen independent phenotype is a typical hallmark characteristic of human prostate cancer development and is largely responsible for late stage castration resistant disease progression. The development of this prostate cancer unique hallmark is mainly mediated by aberrant functioning of androgen receptor and as a consequence of an adaptive response to androgen ablation therapy.

Prostate Cancer Unique Hallmark- Castration Resistance: a late stage aggressive manifestation that results from re-growth of prostate tumor cells that has accustomed to the hormone deprived environment of the prostate [3,4,30]

This hallmark represents a late stage lethal form of prostate cancer that is totally incurable and is mostly accounted for prostate cancer associated deaths with a mean survival time of only 16-18 months. The late appearance of castration resistance hallmark is mainly triggered by modulation of growth factor mediated signaling and an adaptive response to androgen ablation therapy. But other hallmark capabilities also significantly mediate castration resistance disease progression.